Pyrrolidin-2-one derivatives as inhibitors of factor xa

ABSTRACT

The invention relates to compounds of formula (Ic) processes for their preparation, pharmaceutical compositions containing them and to their use in medicine, particularly use in the amelioration of a clinical condition for which a Factor Xa inhibitor is indicated.

FIELD OF THE INVENTION

[0001] The present invention relates to a novel class of chemicalcompounds, to processes for their preparation, to pharmaceuticalcompositions containing them and to their use in medicine, particularlyuse in the amelioration of a clinical condition for which a Factor Xainhibitor is indicated.

BACKGROUND OF THE INVENTION

[0002] Factor Xa is a member of the trypsin-like serine protease classof enzymes. It is a key enzyme in the coagulation cascade. A one-to-onebinding of Factors Xa and Va with calcium ions and phospholipid convertsprothrombin into thrombin. Thrombin plays a central role in themechanism of blood coagulation by converting the soluble plasma protein,fibrinogen, into insoluble fibrin. The insoluble fibrin matrix isrequired for the stabilisation of the primary hemostatic plug. Manysignificant disease states are related to abnormal hemostasis. Withrespect to the coronary arterial vasculature, abnormal thrombusformation due to the rupture of an established atherosclerotic plaque isthe major cause of acute myocardial infarction and unstable angina. Bothtreatment of an occlusive coronary thrombus by thrombolytic therapy andpercutaneous transluminal coronary angioplasty (PTCA) are oftenaccompanied by an acute thrombotic reclosure of the affected vesselwhich requires immediate resolution. With respect to the venousvasculature, a high percentage of patients undergoing major surgery inthe lower extremities or the abdominal area suffer from thrombusformation in the venous vasculature which can result in reduced bloodflow to the affected extremity and a pre-disposition to pulmonaryembolism. Disseminated intravascular coagulopathy commonly occurs withinboth vascular systems during septic shock, certain viral infections andcancer and is characterised by the rapid consumption of coagulationfactors and systemic coagulation which results in the formation oflife-threatening thrombi occurring throughout the vasculature leading towidespread organ failure.

[0003] Beyond its direct role in the formation of fibrin rich bloodclots, thrombin has been reported to have profound bioregulatory effectson a number of cellular components within the vasculature and blood,(Shuman, M. A., Ann. NY Acad. Sci., 405: 349 (1986)).

[0004] A Factor Xa inhibitor may be useful in the treatment of acutevascular diseases such as coronary thrombosis (for example myocardialinfarction and unstable angina), thromboembolism, acute vessel closureassociated with thrombolytic therapy and percutaneous transluminalcoronary angioplasty, transient ischemic attacks, pulmonary embolism,deep vein thrombosis, peripheral arterial occlusion, prevention ofvessel luminal narrowing (restenosis), and the prevention ofthromboembolic events associated with atrial fibrillation, e.g. stroke.They may also have utility as antimagulant agents both in-vivo andex-vivo, and in oedema and inflammation. Thrombin has been reported tocontribute to lung fibroblast proliferation, thus, Factor Xa inhibitorscould be useful for the treatment of some pulmonary fibrotic diseases.Factor Xa inhibitors could also be useful in the treatment of tumourmetastasis, preventing the fibrin deposition and metastasis caused bythe inappropriate activation of Factor Xa by cysteine proteinasesproduced by certain tumour cells. Thrombin can induce neurite retractionand thus Factor Xa inhibitors may have potential in neurogenerativediseases such as Parkinson's and Alzheimer's disease. They have alsobeen reported for use in conjunction with thrombolytic agents, thuspermitting the use of a lower dose of thrombolytic agent.

[0005] The present invention provides novel Factor Xa inhibitors.Compounds of the present invention have oral bioavailability and PKprofiles suitable for acute and chronic therapies.

SUMMARY OF THE INVENTION

[0006] The present invention provides compounds of formula (Ic):

[0007] wherein:

[0008] R¹ represents hydrogen, —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHC₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c),—C₂₋₃alkyl OCONR^(b)R^(c), —C₂₋₃alkylOC₁₋₆alkyl, —C₂₋₃alkylOCH₂phenyl,phenyl or 5- or 6-membered aromatic heterocyclic group containing atleast one heteroatom selected from O, N or S, the phenyl or aromaticheterocyclic group being optionally substituted by one or moresubstitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH, or R¹ represents a group X—W;

[0009] X represents —C₁₋₃alkylene-, propenylene, propynylene;

[0010] W represents —CN, —CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂C₃₋₆alkenyl, phenyl or 5- or 6-membered aromatic ornon-aromatic heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or aromatic or non-aromaticheterocyclic group being optionally substituted by one or moresubstitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0011] R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0012] R^(b) and R^(c) independently represent hydrogen or —C₁₋₄alkyl;

[0013] R² and R³ independently represent hydrogen, —C₁₋₃alkyl or —CF₃,with the proviso that one of R² and R³ is —C₁₋₃alkyl or —CF₃ and theother is hydrogen;

[0014] R⁴ and R⁵, together with the N atom to which they are bonded,form a 4-, 5-, 6-, 7- or 8-membered non-aromatic heterocyclic ring,bridged or unbridged, optionally containing an additional heteroatomselected from O, N or S, and optionally substituted by:

[0015] (i) one or more substitutents selected from: —NH₂, —CF₃, F, —OH,═O, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH,—(C₁₋₃alkyl)NR^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c), —NHSO₂CF₃,—NHSO₂(C₀₋₃alkyl)R^(a), —NHCH₂COCH₂O(C₁₋₃alkyl),—(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —CONHC₂₋₃alkylOH, —CH₂NHC₂₋₃alkylOH,—CH₂OC₁₋₃alkyl, —COCH₂NR^(b)R^(c), —COCH₂N⁺(CH₃)₃ and —CH₂SO₂C₁₋₃alkyl;

[0016] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0017] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkoxy,—C₁₋₆alkylOH, —C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c),—C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylCONR^(b)R^(c) and—C₁₋₃alkylOC₁₋₃alkyl;

[0018] (iii) a group —Y—R^(e),

[0019] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene-, —CO—, —C₁₋₃alkylNH—, —C₁₋₃alkylNHCO—,—C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂— or a direct link,

[0020] R^(e) represents phenyl, a 5- or 6-membered heterocyclecontaining at least one heteroatom selected from O, N or S, or a 5- or6-membered cycloalkyl, each of which is optionally substituted by one ormore substituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; or

[0021] (iv) a second ring R^(f) which is fused to the non-aromaticheterocyclic ring formed by R⁴ and R⁵, wherein R^(f) represents phenyl,a 5- or 6-membered cycloalkyl group or a 5- or 6-membered aromaticheterocyclic group containing at least one heteroatom selected from O, Nor S, and the fused bicyclic group is optionally substituted by one ormore substituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; with the proviso that where thesubstituent on the non-aromatic ring formed by R⁴ and R⁵ is —NH₂, —OH,—C₁₋₆alkoxy, —NHSO₂CF₃, —NHSO₂(C₀₋₃alkyl)R^(a), —NHCOR^(d),—NR^(b)R^(d), —NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e) or—NHC₁₋₃alkyleneR^(e), —NHCH₂COCH₂O(C₁₋₃alkyl), the substituent is notattached to a ring carbon atom adjacent to a heteroatom;

[0022] R⁶ represents:

[0023] (i) a fused bicyclic group —R^(g)R^(h);

[0024] (ii) a group —R^(g)—R^(h);

[0025] (iii) a group -Z-R^(h) wherein Z represents —C₁₋₃alkylene-,—C₂₋₃alkenylene- or a direct link;

[0026] wherein R^(g) and R^(h) independently represent phenyl or a 5- or6-membered aromatic heterocyclic group containing at least oneheteroatom selected from O, N or S, the phenyl or aromatic heterocyclicgroup being optionally substituted by one or more substituents selectedfrom: —C₁₋₃alkyl, —C₁₋₃alkoxy, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;and pharmaceutically acceptable derivatives thereof.

[0027] Further aspects of the invention are:

[0028] A pharmaceutical composition comprising a compound of theinvention together with a pharmaceutical carrier and/or excipient.

[0029] A compound of the invention for use in therapy.

[0030] Use of a compound of the invention for the manufacture of amedicament for the treatment of a patient suffering from a conditionsusceptible to amelioration by a Factor Xa inhibitor.

[0031] A method of treating a patient suffering from a conditionsusceptible to amelioration by a Factor Xa inhibitor comprisingadministering a therapeutically effective amount of a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention provides compounds of formula (I):

[0033] wherein:

[0034] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c),or a group X—W;

[0035] X represents —C₁₋₃alkylene-, propenylene, propynylene;

[0036] W represents —CN, —CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂C₂₋₆alkenyl, —OCONR^(b)R^(c), —OC₁₋₆alkyl,—OCH₂phenyl, phenyl or 5- or 6-membered aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, the phenylor aromatic heterocyclic group being optionally substituted by one ormore substitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0037] R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0038] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0039] R² and R³ independently represent hydrogen, —C₁₋₃alkyl or —CF₃,with the proviso that when one of R² and R³ is —C₁₋₃alkyl or —CF₃, theother is hydrogen;

[0040] R⁴ and R⁵, together with the N atom to which they are bonded,form a 5-, 6- or 7-membered non-aromatic heterocyclic ring, bridged orunbridged, optionally containing an additional heteroatom selected fromO, N or S, and optionally substituted by: (i) one or more substitutentsselected from: —NH₂, —CF₃, F, —OH, ═O, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy,—C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c),—NHSO₂CF₃, —NHSO₂(C₀₋₃alkyl)R^(a) and —(CO₀₋₃alkyl)CO₂C₁₋₃alkyl;

[0041] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0042] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkoxy,—C₁₋₆alkylOH, —C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c),—C₁₋₃alkylCO₂C₁₋₃alkyl or —C₁₋₃alkylCONR^(b)R^(c);

[0043] (iii) a group —Y—R^(e),

[0044] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene-, —CO—, —C₁₋₃alkylNH—, —C₁₋₃alkylNHCO—,—C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂— or a direct link,

[0045] R^(e) represents phenyl, a 5- or 6-membered cycloalkyl or a 5- or6-membered heterocycle containing at least one heteroatom selected fromO, N or S, each of which is optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; or

[0046] (iv) a second ring R^(f) which is fused to the non-aromaticheterocyclic ring formed by R⁴ and R⁵, wherein R^(f) represents phenyl,a 5- or 6-membered cycloalkyl group or a 5- or 6-membered aromaticheterocyclic group containing at least one heteroatom selected from O, Nor S, and the fused bicyclic group is optionally substituted by one ormore substituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0047] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃,—NHSO₂(C₀₋₃alkyl)R^(a), —NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e),—NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), the substituent is notattached to a ring carbon atom adjacent to a heteroatom;

[0048] R⁶ represents:

[0049] (i) a fused bicyclic group —R^(g)R^(h);

[0050] (ii) a group —R^(g)—R^(h);

[0051] (iii) a group -Z-R^(h) wherein Z represents —C₁₋₃alkylene-,—C₂₋₃alkenylene- or a direct link; wherein R^(g) and R^(h) independentlyrepresent phenyl or a 5- or 6-membered aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, each ofwhich is optionally substituted by one or more substituents selectedfrom: —C₁₋₃alkyl, —C₁₋₃alkoxy, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0052] and pharmaceutically acceptable salts or solvates thereof.

[0053] When R¹ represents a group X—W:

[0054] Preferably, X represents —C₁₋₃alkylene-, more preferably-methylene-.

[0055] Preferably, W represents —CN, —CO₂H, —CONR^(b)R^(c),—COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-membered aromatic heterocyclicgroup containing at least one heteroatom selected from O, N or S.

[0056] Preferably, R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or agroup X—W wherein X represents —C₁₋₃alkylene- and W represents —CN,—CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S. More preferably, R¹ represents a group selected fromhydrogen, —CH₂CN, —CH₂CONH₂, —CH₂COC₁₋₆alkyl and —CH₂CO₂C₁₋₆alkyl.

[0057] In another preferred aspect, R¹ represents hydrogen, —C₁₋₆alkyl,—C₃₋₆alkenyl, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a), phenyl or a 5-or 6-membered aromatic heterocycle, or R¹ represents a group X—W whereinX represents —C₁₋₃alkylene- and W represents —CN, —CO₂H, —CONR^(b)R^(c),—COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-membered aromatic ornon-aromatic heterocyclic group containing at least one heteroatomselected from O, N or S. More preferably, R¹ represents hydrogen,—C₁₋₆alkyl, —C₃₋₆alkenyl, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a), orR¹ represents a group X—W wherein X represents —C₁₋₃alkylene- and Wrepresents —CN, —CO₂H, —CONR_(b)R_(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a5- or 6-membered aromatic or non-aromatic heterocyclic group containingat least one heteroatom selected from O, N or S. Even more preferably,R¹ represents a group selected from: hydrogen, —C₁₋₆alkyl, —CH₂CH═CH₂,—CH₂CH₂N(CH₃)₂, —CH₂CH₂NHCOCH₃, —CH₂CN, —CH₂CO₂H, —CH₂CO₂CH₃,—CH₂CO₂t-Butyl, —CH₂CONH₂, —CH₂COCH₂CH₃, —CH₂COt-Butyl, —CH₂CO₂CH₂CH₃,

[0058] Most preferably, R¹ represents a group selected from: hydrogen,—C₁₋₆alkyl, —CH₂CH═CH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂NHCOCH₃, —CH₂CN,—CH₂CO₂H, —CH₂CO₂CH₃, —CH₂CO₂t-Butyl, —CH₂CONH₂, —CH₂COCH₂CH₃,—CH₂COt-Butyl,

[0059] In another preferred aspect, R¹ represents a group selected fromhydrogen, —CH₂CN, —CH₂CONH₂, —CH₂COC₁₋₆alkyl and —CH₂CO₂C₁₋₆alkyl.

[0060] Preferably, R² represents —C₁₋₃alkyl or hydrogen, more preferablymethyl or hydrogen.

[0061] Preferably, R³ represents —C₁₋₃alkyl or hydrogen, more preferablymethyl or hydrogen.

[0062] When the 5-, 6- or 7-membered non-aromatic heterocyclic ringformed by R⁴ and R⁵, optionally containing an additional heteroatom, issubstituted by one or more substituents selected from group (i):

[0063] preferably, the substitutents in group (i) are —NH₂, —CF₃, —OH,—CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) and —NHSO₂CF₃, more preferably —NH₂,—C₁₋₆alkyl, —C₁₋₆alkylOH and —(C₁₋₃alkyl)NR^(b)R^(c).

[0064] When, the 5-, 6- or 7-membered non-aromatic heterocyclic ringformed by R⁴ and R⁵, optionally containing an additional heteroatom, issubstituted —NHCOR^(d):

[0065] preferably, R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl,—C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl. or—C₁₋₃alkylCONR^(b)R^(c), more preferably —C₁₋₃alkylCO₂H,—C₁₋₃alkylNR^(b)R^(c) or —C₁₋₃alkylCO₂C₁₋₃alkyl.

[0066] When, the 5-, 6- or 7-membered non-aromatic heterocyclic ringformed by R⁴ and R⁵, optionally containing an additional heteroatom, issubstituted by —NR^(b)R^(d):

[0067] preferably, R^(b) represents hydrogen;

[0068] preferably, R^(d) represents —C₁₋₆alkyl or —C₁₋₄alkylOH.

[0069] When the 5-, 6- or 7-membered non-aromatic heterocyclic ringformed by R⁴ and R⁵, optionally containing an additional heteroatom, issubstituted by Y—R^(e):

[0070] preferably, Y represents —C₁₋₃alkylene-, —NHCO—,—NHCO₂C₁₋₃alkylene-, —NHC₁₋₃alkylene- or —C₁₋₃alkylNHSO₂—, morepreferably —C₁₋₃alkylene-, —NHCO— or —NHC₁₋₃alkylene-, most preferably—C₁₋₃alkylene-;

[0071] preferably, R^(e) represents imidazole, pyrrole, pyrazole,pyridine, pyrimidine, furan, oxazole, 1,2,4-triazole, phenyl orpyrrolidine, more preferably pyrrole, pyrazole, pyridine, pyrimidine,1,2,4-triazole or pyrrolidine, most preferably pyrrolidine; preferably,R^(e) is unsubstituted or substituted by —C₁₋₃alkyl, —NH₂ or—C₁₋₃alkylOH. A preferred Y—R^(e) is —C₁₋₃alkylene-pyrrolidine.

[0072] When the 5-, 6- or 7-membered non-aromatic heterocyclic ringformed by R⁴ and R⁵, optionally containing an additional heteroatom, Issubstituted by a group (iv):

[0073] preferably, R^(f) represents cyclohexyl. Preferably, R^(f) isunsubstituted.

[0074] Preferably, R⁴ and R⁵, together with the N atom to which they arebonded, form a 5- or 6-membered non-aromatic heterocyclic ring,optionally containing an additional heteroatom selected from O, N or S,and optionally substituted by:

[0075] (i) one or more subsituents selected from: —NH₂, —CF₃, —OH,—CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) and —NHSO₂CF₃;

[0076] (ii) a group —NHCOR^(d) wherein R^(d) represents —C₁₋₆alkyl,—C₂₋₆alkynyl, —C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c),—C₁₋₃alkylCO₂C₁₋₃alkyl or —C₁₋₃alkylCONR^(b)R^(c) or a group —NHR^(d)wherein R^(d) represents —C₁₋₆alkyl or —C₁₋₆alkylOH;

[0077] (iii) a group —Y—R^(e), Y represents —C₁₋₃alkylene-, —NHCO—,—NHCO₂C₁₋₃alkylene-, —NHC₁₋₃alkylene- or —C₁₋₃alkylNHSO₂, R^(e)represents imidazole, pyrrole, pyrazole, pyridine, pyrimidine, furan,oxazole, 1,2,4-triazole, phenyl or pyrrolidine optionally substituted by—C₁₋₃alkyl, —NH₂ or —C₁₋₃alkylOH;

[0078] (iv) a second ring R^(f) which is fused to the non-aromaticheterocyclic ring formed by R⁴ and R⁵, wherein R^(f) representscyclohexyl;

[0079] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃,—NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e) or—NHC₁₋₃alkyleneR^(e), the substituent is not attached to a ring carbonatom adjacent to a heteroatom. More preferably, R⁴ and R⁵, together withthe N atom to which they are bonded, represent piperidine,2-(pyrrolidin-1-ylmethyl)pyrrolidine or morpholine.

[0080] In another preferred aspect, R⁴ and R⁵, together with the N atomto which they are bonded, form a 4-, 5-, 6-, 7- or 8-memberednon-aromatic heterocyclic ring, selected from: piperidine; pyrrolidine;hexamethyleneimine (homopiperidine); morpholine; thiomorpholine;diazepine; tetrahydro-1,6-naphthyridine; 2-azabicyclo[2.2.1]heptane;2-oxa-5-azabicyclo[2.2.1]heptane; 3,7-diazabicyclo[3.3.1]nonane;9-oxa-3,7-diazabicyclo[3.3.1]nonane; 2-azabicyclo[2.2.2]octane;4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepine; 1,2,5,6-tetrahydropyridine;azetidine; 2,5dihydro-1H-pyrrole; piperazine; hexahydropyrimidine;tetrahydroquinoline; decahydroquinoline; tetrahydroquinoxaline;dihydroisoindole; tetrahydroisoquinoline;tetrahydro-5H-imidazo[4,5-c]pyridine;1,3,4,5-tetrahydro-2H-2-benzazepine; 2,5-diazabicyclo[2.2.1]heptane;optionally substituted by:

[0081] (i) one or more substitutents selected from: —NH₂, —CF₃, F, —OH,═O, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c), —NHSO₂CF₃, —NHCH₂COCH₂O (C₁₋₃alkyl),—(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —CONHC₂₋₃alkylOH, —COCH₂NR^(b)R^(c),—COCH₂N⁺(CH₃)₃, —CH₂OC₁₋₃alkyl and —CH₂SO₂C₁₋₃alkyl;

[0082] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0083] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl and —C₁₋₃alkylCONR_(b)R_(c);

[0084] (iii) a group —Y—R^(e),

[0085] Y represents —C₁₋₃alkylene-, —NHCO—, —NHC₁₋₃alkylene-,—NHCO₂C₁₋₃alkylene-, —C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂—, —CO— or a directlink,

[0086] R^(e) represents phenyl, pyridine, pyrrole, isoxazole, pyrazole,pyrrolidine, cyclopentyl, triazole, pyrazine, furan, thiazole,imidazole, morpholine, piperazine, pyrimidine, piperidine, each of whichis optionally substituted by one or more substituents selected from:—C₁₋₃alkyl, halogen, —NH₂;

[0087] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃,—NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e), or —NHC₁₋₃alkyleneR^(e),—NHCO₂C₁₋₃alkyleneR^(e), —NHCH₂COCH₂O(C₁₋₃alkyl), the substituent is notattached to a ring carbon atom adjacent to a heteroatom.

[0088] More preferably R⁴ and R⁵, together with the N atom to which theyare bonded, form a 5-, 6-, 7- or 8-membered non-aromatic heterocyclicring, selected from: piperidine; pyrrolidine; hexamethyleneimine(homopiperidine); morpholine; thiomorpholine; diazepine;tetrahydro-1,6-naphthyridine; 2-azabicyclo[2.2.1]heptane;2-oxa-5-azabicyclo[2.2.1]heptane; 3,7-diazabicyclo[3.3.1]nonane;9-oxa-3,7-diazabicyclo[3.3.1]nonane; 2-azabicyclo[2.2.2]octane;4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepine; 1,2,5,6-tetrahydropyridine;and optionally substituted by:

[0089] (i) one or more substitutents selected from: —NH₂, —CF₃, F, —OH,═O, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —COCH₂NR^(b)R^(c) and —COCH₂N⁺(CH₃)₃;

[0090] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0091] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl and —C₁₋₃alkylCONR^(b)R^(c);

[0092] (iii) a group —Y—R^(e),

[0093] Y represents —C₁₋₃alkylene-, —NHCO—, —NHC₁₋₃alkylene-,—NHCO₂C₁₋₃alkylene-, —C₁₋₃alkylNHSO₂— or a direct link,

[0094] R^(e) represents phenyl, pyridine, pyrrole, isoxazole, pyrazole,pyrrolidine, cyclopentyl, triazole, pyrazine, furan, thiazole,imidazole, morpholine, piperazine, pyrimidine, each of which isoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, halogen, —NH₂; with the proviso that where the substituenton the non-aromatic ring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy,—NHCOR^(d), —NR^(b)R^(d), —NHCOR^(a), or —NHC₁₋₃alkyleneR^(e),—NHCO₂C₁₋₃alkyleneR^(e), the substituent is not attached to a ringcarbon atom adjacent to a heteroatom;

[0095] Even more preferably R⁴ and R⁵, together with the N atom to whichthey are bonded, form a 5-, 6-, 7-, 8-membered non-aromatic heterocyclicring, selected from: piperidine; pyrrolidine; hexamethyleneimine(homopiperidine); morpholine; thiomorpholine; diazepine;tetrahydro-1,6-naphthyridine; 2-azabicyclo[2.2.1]heptane;2-oxa-5-azabicyclo[2.2.1]heptane; 3,7-diazabicyclo[3.3.1]nonane;9-oxa-3,7-diazabicyclo[3.3.1]nonane; 2-azabicyclo[2.2.2]octane;optionally substituted by a subsituent selected from: —CH₃, ═O, —NH₂, F,—CH₂OH, —CH₂CH₂NHCH₃, —NHCOC₁₋₃alkyl, —NHCOC≡CH, —NHCOCH₂CH₂CO₂H;—NHCOCH₂N(CH₃)₂, —NHCOC₁₋₃alkylCO₂CH₃,

[0096] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, NHCO₂C₁₋₃alkyleneR^(e), —NHCO— or—NHCH₂— the substituent is not attached to a ring carbon atom adjacentto a heteroatom.

[0097] When R⁶ represents a fused bicyclic group —R^(g)R^(h):

[0098] Preferably, R^(g) represents phenyl or thiophene, more preferablyphenyl. Preferably, R^(g) is unsubstituted. When R^(g) is thiophene,preferably it is attached to the sulphonyl group at the 2-position.

[0099] Preferably, R^(h) represents phenyl. Preferably, R^(h) Issubstituted by halogen, more preferably Cl. Preferably, R^(h) ismonosubstituted.

[0100] When R⁶ represents a group —R^(g)—R^(h):

[0101] Preferably, R^(g) represents thiophene or phenyl, more preferablythiophene. Preferably, R^(g) is unsubstituted. When R⁹ is thiophene,preferably it is attached to the sulphonyl group at the 2-position.

[0102] Preferably, R^(h) represents thiophene or phenyl, more preferablythiophene. Preferably, R^(h) is substituted by halogen, more preferablyCl. Preferably, R^(h) is monosubstituted.

[0103] When R⁶ represents a group -Z-R^(h):

[0104] Preferably, Z represents —C₂₋₃alkenyl-, more preferably —CH═CH—.

[0105] Preferably, R^(h) represents phenyl. Preferably, R^(h) issubstituted by halogen, more preferably Cl. Preferably, R^(h) ismonosubstituted.

[0106] (iii) In another preferred aspect, R⁶ represents:

[0107] (i) a fused bicyclic group —R^(g)R^(h) wherein R^(g) representsphenyl, thiophene, imidazole, thiazole, pyrrole or furan optionallysubstituted by one or more substituents selected from: —C₁₋₃alkyl andR^(h) represents phenyl or pyridine optionally substituted by one ormore substituents selected from: halogen and —OH;

[0108] (ii) a group —R^(g)—R^(h) wherein R^(g) represents thiophene orphenyl and R^(h) represents phenyl, pyridine, thiophene, thiadiazole,tetrazole, isoxazole or furan optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, halogen, —NH₂, —OC₁₋₃alkyl and—OH;

[0109] (iii) a group -Z-R^(h) wherein Z represents —C₂₋₃alkenylene- or adirect link wherein R^(h) represents phenyl or thiophene optionallysubstituted by one or more substituents selected from: halogen, OH and—CN;

[0110] Preferably, R⁶ represents a substituent selected from:

[0111] More preferably, R⁶ represents a substituent selected from:

[0112] Even more preferably, R⁶ represent a substituent selected from:

[0113] Most preferably, R⁶ represents (chlorothienyl)ethene.

[0114] In another preferred aspect of the invention, R⁶ representschloronaphthylene, chlorobenzothiophene, chlorobithiophene orchlorophenylethene. More preferably, A represents a group selected from:6-chloronaphthyl, 5′-chloro-2,2′-biothiophene, (4-chlorophenyl)ethene,6-chloro-1-benzothiophene.

[0115] It is to be understood that the present invention covers allcombinations of suitable, convenient and preferred groups describedhereinabove.

[0116] Hence, in a preferred aspect the invention provides compounds offormula (I) wherein:

[0117] R¹ represents hydrogen, —C₁₋₆alkyl, —C₃₋₆alkenyl,—C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a), phenyl or a 5- or 6-memberedaromatic heterocycle, or R¹ represents a group X—W wherein X represents—C₁₋₃alkylene- and W represents —CN, —CO₂H, —CONR^(b)R^(c),—COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-membered aromatic ornon-aromatic heterocyclic group containing at least one heteroatomselected from O, N or S.

[0118] R² and R³ independently represent hydrogen, or —C₁₋₃alkyl, withthe proviso that one of R² and R³ is —C₁₋₃alkyl and the other ishydrogen;

[0119] R⁴ and R⁵, together with the N atom to which they are bonded,form a 4-, 5-, 6-, 7- or 8-membered non-aromatic heterocyclic ring,selected from: piperidine; pyrrolidine; hexamethyleneimine(homopiperidine); morpholine; thiomorpholine; diazepine;tetrahydro-1,6-naphthyridine; 2-azabicyclo[2.2.1]heptane;2-oxa-5-azabicyclo[2.2.1]heptane; 3,7-diazabicyclo[3.3.1]nonane;9-oxa-3,7-diazabicyclo[3.3.1]nonane; 2-azabicyclo[2.2.2]octane;4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepine; 1,2,5,6-tetrahydropyridine;azetidine; 2,5-dihydro-1H-pyrrole; piperazine; hexahydropyrimidine;tetrahydroquinoline; decahydroquinoline; tetrahydroquinoxaline;dihydroisoindole; tetrahydroisoquinoline;tetrahydro-5H-imidazo[4,5c]pyridine;1,3,4,5-tetrahydro-2H-2-benzazepine; 2,5-diazabicyclo[2.2.1]heptane;3,5,6,7,-tetrahydro-4H-[1,2,3]triazolo[4,5b]pyridine;2,3-dihydro-1H-indole; optionally substituted by:

[0120] (i) one or more substitutents selected from: —NH₂, —CF₃, F, —OH,═O, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c), —NHSO₂CF₃, —NHCH₂COCH₂O(C₁₋₃alkyl),—(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —CONHC₂₋₃alkylOH, —COCH₂NR^(b)R^(c),—COCH₂N⁺(CH₃)₃, —CH₂OC₁₋₃alkyl and —CH₂SO₂C₁₋₃alkyl;

[0121] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0122] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl and —C₁₋₃alkylCONR^(b)R^(c);

[0123] (iii) a group —Y—R^(e),

[0124] Y represents —C₁₋₃alkylene-, —NHCO—, —NHC₁₋₃alkylene-,—NHCO₂C₁₋₃alkylene-, —C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂—,—CO— or a direct link,

[0125] R^(e) represents phenyl, pyridine, pyrrole, isoxazole, pyrazole,pyrrolidine, cyclopentyl, triazole, pyrazine, furan, thiazole,imidazole, morpholine, piperazine, pyrimidine, piperidine, each of whichis optionally substituted by one or more substituents selected from:—C₁₋₃alkyl, halogen, —NH₂;

[0126] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃,—NHCOR_(d), —NR^(b)R^(d), —NHCOR^(e), or —NHC₁₋₃alkyleneR^(e),—NHCO₂C₁₋₃alkyleneR^(e), —NHCH₂COCH₂O(C₁₋₃alkyl), the substituent is notattached to a ring carbon atom adjacent to a heteroatom;

[0127] R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0128] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0129] R⁶ represents:

[0130] (i) a fused bicyclic group —R^(g)R^(h) wherein R^(g) representsphenyl, thiophene, imidazole, thiazole, pyrrole or furan optionallysubstituted by one or more substituents selected from: —C₁₋₃alkyl andR^(h) represents phenyl or pyridine optionally substituted by one ormore substituents selected from: halogen and —OH;

[0131] (ii) a group —R^(g)—R^(h) wherein R^(g) represents thiophene orphenyl and R^(h) represents phenyl, pyridine, thiophene, thiadiazole,tetrazole, isoxazole or furan optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, halogen, —NH₂, —OC₁₋₃alkyl and—OH;

[0132] (iii) a group -Z-R^(h) wherein Z represents —C₂₋₃alkenylene- or adirect link wherein R^(h) represents phenyl or thiophene optionallysubstituted by one or more substituents selected from: halogen, OH and—CN;

[0133] and pharmaceutically acceptable salts or solvates thereof.

[0134] In a more preferred aspect the invention provides compounds offormula (I) wherein:

[0135] R¹ represents hydrogen, —C₁₋₆alkyl, —C₁₋₃alkenyl,—C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a), phenyl or a 5- or 6-memberedaromatic heterocycle, or R¹ represents a group X—W wherein X represents—C₁₋₃alkylene- and W represents —CN, —CO₂H, —CONR^(b)R^(c),—COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5 or 6-membered aromatic ornon-aromatic heterocyclic group containing at least one heteroatomselected from O, N or S.

[0136] R² and R³ independently represent hydrogen, or —C₁₋₃alkyl, withthe proviso that one of R² and R³ is —C₁₋₃alkyl and the other ishydrogen;

[0137] R⁴ and R⁵, together with the N atom to which they are bonded,form a 4-, 5-, 6-, 7- or 8-membered non-aromatic heterocyclic ring,selected from: piperidine; pyrrolidine; hexamethyleneimine(homopiperidine); morpholine; thiomorpholine; diazepine;tetrahydro-1,6-naphthyridine; 2-azabicyclo[2.2.1]heptane;2-oxa-5-azabicyclo[2.2.1]heptane; 3,7-diazabicyclo[3.3.1]nonane;9-oxa-3,7-diazabicyclo[3.3.1]nonane; 2-azabicyclo[2.2.2]octane;4,6,7,8-tetrahydro-5h-thieno[3,2-c]azepine; 1,2,5,6-tetrahydropyridine;azetidine; 2,5-dihydro-1h-pyrrole; piperazine; hexahydropyrimidine;tetrahydroquinoline; decahydroquinoline; tetrahydroquinoxaline;dihydroisoindole; tetrahydroisoquinoline;tetrahydro-5h-imidazo[4,5-c]pyridine;1,3,4,5-tetrahydro-2h-2-benzazepine; 2,5-diazabicyclo[2.2.1]heptane;optionally substituted by:

[0138] (i) one or more substitutents selected from: —NH₂, —CF₃, F, —OH,═O, —C₁₋₆alkyl, —C₁₋₃alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c), —NHSO₂CF₃, —NHCH₂COCH₂O(C₁₋₃alkyl),—(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —CONHC₂₋₃alkylOH, —COCH₂NR^(b)R^(c),—COCH₂N⁺(CH₃)₃, —CH₂OC₁₋₃alkyl and —CH₂SO₂C₁₋₃alkyl;

[0139] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0140] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl,—C₁₋₃alkylOC₁₋₃alkyl and —C₁₋₃alkylCONR^(b)R^(c);

[0141] (iii) a group —Y—R^(e),

[0142] Y represents —C₁₋₃alkylene-, —NHCO—, —NHC₁₋₃alkylene-,—NHCO₂C₁₋₃alkylene-, —C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂,—CO— or a directlink,

[0143] R^(e) represents phenyl, pyridine, pyrrole, isoxazole, pyrazole,pyrrolidine, cyclopentyl, triazole, pyrazine, furan, thiazole,imidazole, morpholine, piperazine, pyrimidine, piperidine, each of whichis optionally substituted by one or more substituents selected from:—C₁₋₃alkyl, halogen, —NH₂;

[0144] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃,—NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e), or —NHC₁₋₃alkyleneR^(e),—NHCO₂C₁₋₃alkyleneR^(e), —NHCH₂COCH₂O(C₁₋₃alkyl), the substituent is notattached to a ring carbon atom adjacent to a heteroatom;

[0145] R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0146] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0147] R⁸ represents a substituent selected from:

[0148] and pharmaceutically acceptable salts or solvates thereof.

[0149] In an even more preferred aspect the invention provides compoundsof formula (I) wherein:

[0150] R¹ represents a group selected from: hydrogen, —C₁₋₆alkyl,—CH₂CH═CH₂, —CH₂CH₂N(CH₃)₂, —CH₂CH₂NHCOCH₃, —CH₂CN, —CH₂CO₂H,—CH₂CO₂CH₃, —CH₂CO₂t-Butyl, —CH₂CONH₂, —CH₂COCH₂CH₃, —CH₂COt-Butyl,

[0151] R² and R³ independently represent hydrogen, or —C₁₋₃alkyl, withthe proviso that one of R² and R³ is —C₁₋₃alkyl and the other ishydrogen;

[0152] R⁴ and R⁵, together with the N atom to which they are bonded,form a 5-, 6-, 7-, 8-membered non-aromatic heterocyclic ring, selectedfrom: piperidine; pyrrolidine; hexamethyleneimine (homopiperidine);morpholine; thiomorpholine; diazepine; tetrahydro-1,6-naphthyridine;2-azabicyclo[2.2.1]heptane; 2-oxa-5-azabicyclo[2.2.1 ]heptane;3,7-diazabicyclo[3.3.1]nonane; 9-oxa-3,7-diazabicyclo[3.3.1]nonane;2-azabicyclo[2.2.2]octane; optionally substituted by a subsituentselected from: —CH₃, ═O, —NH₂, F, —CH₂OH, —CH₂CH₂NHCH₃, —NHCOC₁₋₃alkyl,—NHCOC≡CH, —NHCOCH₂CH₂CO₂H; —NHCOCH₂N(CH₃)₂, —NHCOC₁₋₃alkylCO₂CH₃,

[0153] with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, NHCO₂C₁₋₃alkyleneR^(e), —NHCO— or—NHCH₂— the substituent is not attached to a ring carbon atom adjacentto a heteroatom;

[0154] R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5 or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0155] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0156] R⁶ represent a substituent selected from:

[0157] and pharmaceutically acceptable salts or solvates thereof.

[0158] The present invention also provides compounds of formula (Ia):

[0159] wherein:

[0160] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—W,wherein X represents —C₁₋₃alkylene- and W represents —CN, —CO₂H,—CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl, phenyl or 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S, the phenyl or aromatic heterocyclic group beingoptionally substituted by one or more substitutents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0161] R² and R³ independently represent hydrogen, —C₁₋₃alkyl or CF₃with the proviso that when one of R² and R³ is —C₁₋₃alkyl or CF₃, theother is hydrogen;

[0162] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0163] A represents a group selected from:

[0164] Z represents an optional substituent halogen,

[0165] alk represents alkylene or alkenylene,

[0166] T represents a heteroatom selected from S or N;

[0167] B represents one or more optional substituents on ring carbonatoms selected from: (i) one or more substituents selected from —CF₃,—F, ═O, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) and —(C₀₋₃alkyl)CO₂C₁₋₃alkyl;

[0168] (ii) a group —Y—R^(e),

[0169] Y represents —C₁₋₃alkylene-, —CO—, —C₁₋₃alkylNH—,—C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂— or a direct link,

[0170] R^(e) represents phenyl, a 5- or 6-membered cycloalkyl or a 5- or6-membered heterocycle containing at least one heteroatom selected fromO, N or S, each of which is optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; or

[0171] (iii) a second ring R^(f) which is fused to the heterocyclicring, wherein R^(f) represents phenyl, a 5- or 6-membered cycloalkylgroup or a 5- or 6-membered aromatic heterocyclic group containing atleast one heteroatom selected from O, N or S, and the fused bicyclicgroup is optionally substituted by one or more substituents selectedfrom: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂,—CO₂H and —OH;

[0172] and pharmaceutically acceptable salts and solvates thereof.

[0173] The present invention also provides compounds of formula (Ib):

[0174] wherein:

[0175] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—W,wherein X represents —C₁₋₃alkylene- and W represents —CN, —CO₂H,—CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl, phenyl or 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S, the phenyl or aromatic heterocyclic group beingoptionally substituted by one or more substitutents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0176] R² and R³ independently represent hydrogen, —C₁₋₃alkyl or CF₃with the proviso that when one of R² and R³ is —C₁₋₃alkyl or CF₃, theother is hydrogen;

[0177] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0178] A represents a group selected from:

[0179] Z represents an optional substituent halogen,

[0180] alk represents alkylene or alkenylene,

[0181] T represents a heteroatom selected from S or N;

[0182] n represents 0 or 1;

[0183] B represents one or more optional substituents on ring carbonatoms selected from:

[0184] (i) one or more substitutents selected from: —NH₂, —CF₃, F, —OH,═O, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH,—(C₁₋₃alkyl)N^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c), —NHSO₂CF₃,—NHSO₂(C₀₋₃alkyl)R^(a) and —(CO₃alkyl)CO₂C₁₋₃alkyl;

[0185] R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0186] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0187] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkoxy,—C₁₋₆alkylOH, —C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c),—C₁₋₃alkylCO₂C₁₋₃alkyl or —C₁₋₃alkylCONR^(b)R^(c);

[0188] (iii) a group —Y—R^(e),

[0189] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene-, —CO—, —C₁₋₃alkylNH—, —C₁₋₃alkylNHCO—,—C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂— or a direct link,

[0190] R^(e) represents phenyl, a 5- or 6-membered cycloalkyl or a 5- or6-membered heterocycle containing at least one heteroatom selected fromO, N or S, each of which is optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; or

[0191] (iv) a second ring R^(f) which is fused to the heterocyclic ring,wherein R^(f) represents phenyl, a 5- or 6-membered cycloalkyl group ora 5- or 6-membered aromatic heterocyclic group containing at least oneheteroatom selected from O, N or S, and the fused bicyclic group isoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH;

[0192] with the proviso that where B is —NH₂, —OH, —C₁₋₆alkoxy,—NHSO₂CF₃, —NHSO₂(C₀₋₃alkyl)R^(a), —NHCOR^(d), —NR^(b)R^(e), —NHCOR^(e),—NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), it is not attached to aring carbon atom adjacent to a heteroatom;

[0193] and pharmaceutically acceptable derivatives thereof.

[0194] The present invention also provides compounds of formula (I)wherein:

[0195] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₆alkylOH, —C₂₋₆alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c) ora group X—W;

[0196] X represents —C₁₋₃alkylene-, propenylene, propynylene;

[0197] W represents —CN, —CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂C₂₋₆alkenyl, —OCONR^(b)R^(c), —OC₁₋₆alkyl,—OCH₂phenyl, phenyl or 5- or 6-membered aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, the phenylor aromatic heterocyclic group being optionally substituted by one ormore substitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0198] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0199] R⁴ and R⁵, together with the N atom to which they are bonded,form a 5- or 6-membered non-aromatic heterocyclic ring, optionallycontaining an additional heteroatom, and optionally substituted by:

[0200] (i) one or more substituents selected from —NH₂, —CF₃, —OH,—CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) and NHSO₂CF₃;

[0201] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0202] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂CH₃ or—C₁₋₃alkylCONR^(b)R^(c);

[0203] (iii) a group —Y—R^(e),

[0204] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene- or —C₁₋₃alkylNHSO₂—,

[0205] R^(e) represents imidazole, pyrrole, pyrazole, pyridine,pyrimidine, furan, oxazole, 1,2,4-triazole, phenyl or pyrrolidineoptionally substituted by —C₁₋₃alkyl, NH₂ or —C₁₋₃alkylOH; with theproviso that where the substituent on the non-aromatic ring formed by R⁴and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃, —NHCOR^(d), —NR^(b)R^(d),—NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), thesubstituent is not attached to a ring carbon atom adjacent to aheteroatom;

[0206] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0207] R⁶ represents a group selected from:

[0208] Z represents an optional substituent halogen,

[0209] alk represents alkylene or alkenylene,

[0210] T represents a heteroatom selected from S or N;

[0211] The present invention also provides compounds of formula (I)wherein:

[0212] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—Wwherein X represents —C₁₋₃alkylene- and W represents —CN, —CO₂H,—CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S;

[0213] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0214] R⁴ and R⁵, together with the N atom to which they are bonded,form a 5 or 6-membered non-aromatic heterocyclic ring, optionallycontaining an additional heteroatom, and optionally substituted by:

[0215] (i) one or more substituents selected from —NH₂, —CF₃, —OH,—CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) and —NHSO₂CF₃;

[0216] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0217] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₆alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂CH₃ or—C₁₋₃alkylCONR^(b)R^(c),

[0218] (iii) a group —Y—R^(e),

[0219] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene- or—NHC₁₋₃alkylene-, —C₁₋₃alkylNHSO₂—,

[0220] R^(e) represents imidazole, pyrrole, pyrazole, pyridine,pyrimidine, furan, oxazole, 1,2,4-triazole, phenyl or pyrrolidineoptionally substituted by —C₁₋₃alkyl, NH₂ or —C₁₋₃alkylOH; with theproviso that where the substituent on the non-aromatic ring formed by R⁴and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃, —NHCOR^(d), —NR^(b)R^(d),—NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), thesubstituent is not attached to a ring carbon atom adjacent to aheteroatom;

[0221] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0222] R⁶ represents a group selected from:

[0223] Z represents an optional substituent halogen,

[0224] alk represents alkylene or alkenylene,

[0225] T represents a heteroatom selected from S or N;

[0226] The present invention also provides compounds of formula (I)wherein:

[0227] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkyNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c) ora group X—W;

[0228] X represents —C₁₋₃alkylene-, propenylene, propynylene;

[0229] W represents —CN, —CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂C₂₋₆alkenyl, —OCONR^(b)R^(c), —OC₁₋₆alkyl,—OCH₂phenyl, phenyl or 5- or 6-membered aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, the phenylor aromatic heterocyclic group being optionally substituted by one ormore substitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0230] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0231] R⁴ and R⁵, together with the N atom to which they are bonded,represent piperidine, 2-(pyrrolidin-1-ylmethyl)pyrrolidine ormorpholine;

[0232] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0233] R⁶ represents a group selected from:

[0234] Z represents an optional substituent halogen,

[0235] alk represents alkylene or alkenylene,

[0236] T represents a heteroatom selected from S or N;

[0237] The present invention also provides compounds of formula (I)wherein:

[0238] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c) ora group X—W;

[0239] X represents —C₁₋₃alkylene-, propenylene, propynylene;

[0240] W represents —CN, —CO₂H, —CONR_(b)R_(c), —COC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂C₂₋₆alkenyl, —OCONR^(b)R^(c), —OC₁₋₆alkyl,—OCH₂phenyl, phenyl or 5- or 6-membered aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, the phenylor aromatic heterocyclic group being optionally substituted by one ormore substitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0241] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0242] R⁴ and R⁵, together with the N atom to which they are bonded,form a 5- or 6-membered non-aromatic heterocyclic ring, optionallycontaining an additional heteroatom, and optionally substituted by:

[0243] (i) one or more substituents selected from —NH₂, —CF₃, —OH,—CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) or —NHSO₂CF₃;

[0244] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0245] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₆alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂CH₃ or—C₁₋₃alkylCONR^(b)R^(c),

[0246] (iii) a group —Y—R^(e),

[0247] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene- or —C₁₋₃alkylNHSO₂—,

[0248] R^(e) represents imidazole, pyrrole, pyrazole, pyridine,pyrimidine, furan, oxazole, 1,2,4-triazole, phenyl or pyrrolidineoptionally substituted by —C₁₋₃alkyl, NH₂ or —C₁₋₃alkylOH; with theproviso that where the substituent on the non-aromatic ring formed by R⁴and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃, —NHCOR^(d), —NR^(b)R^(d),—NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), thesubstituent is not attached to a ring carbon atom adjacent to aheteroatom;

[0249] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0250] R⁶ represents 6-chloronaphthyl, 5′-chloro-2,2′-bithiophene,(4-chlorophenyl)ethene or 6-chloro-1-benzothiophene.

[0251] The present invention also provides compounds of formula (I)wherein:

[0252] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—Wwherein X represents —C₁₋₃alkylene- and W represents —CN, —CO₂H,—CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S;

[0253] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0254] R⁴ and R⁵, together with the N atom to which they are bonded,represent piperidine, 2-(pyrrolidin-1-ylmethyl)pyrrolidine ormorpholine,

[0255] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl,

[0256] R⁶ represents a group selected from:

[0257] Z represents an optional substituent halogen,

[0258] alk represents alkylene or alkenylene,

[0259] T represents a heteroatom selected from S or N;

[0260] The present invention also provides compounds of formula (I)wherein:

[0261] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—Wwherein X represents —C₁₋₃alkylene- and W represents —CN, —CO₂H,—CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S;

[0262] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0263] R⁴ and R⁵, together with the N atom to which they are bonded,form a 5- or 6-membered non-aromatic heterocyclic ring, optionallycontaining an additional heteroatom, and optionally substituted by:

[0264] (i) one or more substituents selected from —NH₂, —CF₃, —OH,—CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c),—(C₀₋₃alkyl)CONR^(b)R^(c) and —NHSO₂CF₃;

[0265] (ii) a group —NHCOR^(d) or —NR^(b)R^(d),

[0266] R^(d) represents —C₁₋₆alkyl, —C₂₋₆alkynyl, —C₁₋₆alkylOH,—C₁₋₆alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂CH₃ or—C₁₋₃alkylCONR^(b)R^(c),

[0267] (iii) a group —Y—R^(e),

[0268] Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene- or —C₁₋₃alkylNHSO₂—,

[0269] R^(e) represents imidazole, pyrrole, pyrazole, pyridine,pyrimidine, furan, oxazole, 1,2,4-triazole, phenyl or pyrrolidineoptionally substituted by —C₁₋₃alkyl, NH₂ or —C₁₋₃alkylOH; with theproviso that where the substituent on the non-aromatic ring formed by R⁴and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃, —NHCOR^(d), —NR^(b)R^(d),—NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), thesubstituent is not attached to a ring carbon atom adjacent to aheteroatom;

[0270] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;

[0271] R⁶ represents 6-chloronaphthyl, 5′-chloro-2,2′-bithiophene,(4-chlorophenyl)ethene or 6-chloro-1-benzothiophene.

[0272] The present invention also provides compounds of formula (I)wherein:

[0273] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c) ora group X—W;

[0274] X represents —C₁₋₃alkylene-, propenylene, propynylene;

[0275] W represents —CN, —CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl,—CO₂C₁₋₆alkyl, —CO₂C₂₋₆alkenyl, —OCONR^(b)R^(c), —OC₁₋₆alkyl,—OCH₂phenyl, phenyl or 5- or 6-membered aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, the phenylor aromatic heterocyclic group being optionally substituted by one ormore substitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;

[0276] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0277] R⁴ and R⁵, together with the N atom to which they are bonded,represent piperidine, 2-(pyrrolidin-1-ylmethyl)pyrrolidine ormorpholine;

[0278] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl,

[0279] R⁶ represents 6-chloronaphthyl, 5′-chloro-2,2′-bithiophene,(4-chlorophenyl)ethene or 6-chloro-1-benzothiophene.

[0280] The present invention also provides compounds of formula (I)wherein:

[0281] R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—Wwherein X represents —C₁₋₃alkylene- and W represents —CN, —CO₂H,—CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-memberedaromatic heterocyclic group containing at least one heteroatom selectedfrom O, N or S;

[0282] R² and R³ independently represent hydrogen or —C₁₋₃alkyl, withthe proviso that when one of R² and R³ is —C₁₋₃alkyl, the other ishydrogen;

[0283] R⁴ and R⁵, together with the N atom to which they are bonded,represent piperidine, 2-(pyrrolidin-1-ylmethyl)pyrrolidine ormorpholine,

[0284] R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl,

[0285] R⁶ represents 6-chloronaphthyl, 5′-chloro-2,2′-bithiophene,(4-chlorophenyl)ethene or 6-chloro-1-benzothiophene.

[0286] The compounds of formula (I), (Ia), (Ib), (Ic) contain chiral(asymmetric) centres. The individual stereoisomers (enantiomers anddiastereoisomers) and mixtures of these are within the scope of thepresent invention.

[0287] As used herein, the terms “alkyl” and “alkoxy” mean both straightand branched chain saturated hydrocarbon groups. Examples of alkylgroups include methyl (—CH₃), ethyl (—C₂H₅), propyl (—C₃H₇) and butyl(—C₄H₉). Examples of alkoxy groups include methoxy (—OCH₃) and ethoxy(—OC₂H₅).

[0288] As used herein, the term “alkylene” means both straight andbranched chain saturated hydrocarbon linker groups. Examples of alkylenegroups include methylene (—CH₂—) and ethylene (—CH₂CH₂—).

[0289] As used herein, the term “alkenyl” means both straight andbranched chain unsaturated hydrocarbon groups, wherein the unsaturationis present only as double bonds. Examples of alkenyl groups includeethenyl (—CH═CH₂) and propenyl (—CH═CHCH₃ or —CH₂CH═CH₂).

[0290] As used herein, the term “alkenylene” means both straight andbranched chain unsaturated hydrocarbon linker groups, wherein theunsaturation is present only as double bonds. Examples of alkenylenegroups includes ethenylene (—CH═CH—) and propenylene (—CH₂—CH═CH— or—CH═CH—CH₂—).

[0291] As used herein, the term “alkynyl” means both straight andbranched chain unsaturated hydrocarbon groups, wherein the unsaturationis present only as triple bonds. Examples of alkynyl groups includepropynyl (e.g. —CH₂—C≡CH, —C≡C—CH₃).

[0292] As used herein, the term “propynylene” means a straight chainunsaturated hydrocarbon linker group, wherein the unsaturation ispresent as a triple bond (—CH₂—C≡C—).

[0293] As used herein, the term “halogen” means fluorine, chlorine,bromine and iodine.

[0294] As used herein, the term “dycloalkyl group” means an aliphaticring (a saturated carbocyclic group). Examples of cycloalkyl groupsinclude cyclopentyl and cyclohexyl.

[0295] As used herein, the term “heterocyclic group” means ringscontaining one or more heteroatoms selected from: N, S and O. Theheterocycle may be aromatic or non-aromatic, i.e., may be saturated,partially or fully unsaturated. Examples of 5-membered groups includethienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyland furanyl, 6-membered groups include pyridyl, pyrazyl and pyrimidyl,morpholinyl, thiomorpholinyl, 7-membered groups include azepinyl.

[0296] As used herein, the term “pharmaceutically acceptable” means acompound which is suitable for pharmaceutical use.

[0297] As used herein, the term “pharmaceutically acceptablederivative”, means any pharmaceutically acceptable salt, solvate, orprodrug e.g. ester or carbamate, or salt or solvate of such a prodrug,of a compound of formula (I), (Ia), (Ib), or (Ic), which uponadministration to the recipient is capable of providing (directly orindirectly) a compound of formula (I), (Ia), (Ib), or (Ic), or an activemetabolite or residue thereof. Preferred pharmaceutically acceptablederivatives are salts and solvates.

[0298] Suitable salts according to the invention include those formedwith both organic and inorganic acids and bases. Pharmaceuticallyacceptable acid addition salts include those formed from mineral acidssuch as: hydrochloric, hydrobromic, sulphuric, phosphoric, acid; andorganic acids such as: citric, tartaric, lactic, pyruvic, acetic,trifluoroacefic, succinic, oxalic, formic, fumaric, maleic, oxaloacetic,methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonicand isethionic acids. Pharmaceutically acceptable base salts includeammonium salts, alkali metal salts such as those of sodium andpotassium, alkaline earth metal salts such as those of calcium andmagnesium and salts with organic bases, including salts of primary,secondary and tertiary amines, such as isopropylamine, diethylamine,ethanolamine, trimethylamine, dicyclohexyl amine andN-methyl-D-glucamine. Particularly preferred pharmaceutically acceptablesalts include those formed from hydrochloric, trifluoroacetic and formicacids.

[0299] Those skilled in the art of organic chemistry will appreciatethat many organic compounds can form complexes with solvents in whichthey are reacted or from which they are precipitated or crystallized.These complexes are known as δsolvates”. For example, a complex withwater is known as a “hydrate”. Solvates of the compound of formula (I),(Ia), (Ib), or (Ic) are within the scope of the invention.

[0300] Salts and solvates of compounds of formula (I), (Ia), (Ib), or(Ic) which are suitable for use in medicine are those wherein thecounterion or associated solvent is pharmaceutically acceptable.However, salts and solvates having non-pharmaceutically acceptablecounterions or associated solvents are within the scope of the presentinvention, for example, for use as intermediates in the preparation ofother compounds of formula (I), (Ia), (Ib), or (Ic) and theirpharmaceutically acceptable salts and solvates.

[0301] As used herein, the term “prodrug” means a compound which isconverted within the body, e.g. by hydrolysis in the blood, into itsactive form that has medical effects. Pharmaceutically acceptableprodrugs are described in T. Higuchi and V. Stella, Prodrugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in EdwardB. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference. Esters may be active in their ownright and /or be hydrolysable under in vivo conditions in the humanbody. Suitable pharmaceutically acceptable in vivo hydrolysable estergroups include those which break down readily in the human body to leavethe parent acid or its salt.

[0302] Preferred compounds of the invention include:

[0303]6-Chloro-N{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0304]6-Chloro-N{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0305]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{2-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-1-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate;

[0306]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[2-(morpholin-4-ylmethyl)pyrrolidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0307]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0308]6-Chloro-N-{(3S)-1-[(1S)-2-(2,6-dimethylmorpholin-4-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0309]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0310]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0311]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0312]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{2-[(methylsulfonyl)methyl]morpholin-4-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0313]6-Chloro-N-((3S)-{(1S)-2-[2-(methoxymethyl)morpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0314]4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-methylmorpholine-2-carboxamide;

[0315]4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyI]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-(2-hydroxypropyl)morpholine-2-carboxamide;

[0316]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0317]6-Chloro-N-{(3S)-1-[(1S)-2-(2-{[(2-hydroxypropyl)amino]methyl}morpholin-4yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;

[0318]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(dimethylamino)methyl]morpholin-4-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate;

[0319]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(piperidin-1-ylmethyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0320]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0321]6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0322]6-Chloro-N-{(3S)-1-[(1S)-2-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0323]N-{(3S)-1-[(1S)-2-Azetidin-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0324]6-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydro-1,6-naphthyridin-1-(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0325]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0326]N-((3S)-1-{(1S)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;

[0327]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;

[0328]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;

[0329]N-{1-[(1S)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0330]N-{(3S)-1-[(1S)-2-(2-Azabicyclo[2.2.2]oct-2-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0331]6-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0332]6-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0333]6-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0334]6-Chloro-N-((3R)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0335]6-Chloro-N-[(3R)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0336]5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;

[0337](E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)ethenesulfonamideformate;

[0338]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0339]5-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0340]N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0341]N2-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0342]N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0343](E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0344](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide;

[0345] MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0346]N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0347]N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0348]N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0349]6-Chloro-N-((3S)-1-{(1S)-2-[2-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0350]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-phenylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0351]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0352]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N,N-dimethylprolinamide;

[0353] Methyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-L-prolinate;

[0354]6-Chloro-N-((3S)-1-{(1S)-2-[4-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0355] Methyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)suffonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-3-carboxylate;

[0356]N-{(3S)-1-[(1S)-2-(4-Acetylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0357]6-Chloro-N-((3S)-1-{(1S)-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0358]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylpyrrolidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0359]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]prolinamide;

[0360]6-Chloro-N-{(3S)-1-[(1S)-2-(3-isopropyltetrahydropyrimidin-1(2H)-yl)-1-methyl-2-oxothyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0361]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2S)-2-(morpholin-4-ylmethyl)pyrrolidin-1-yl]-2-oxoethyl)-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0362]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(4,6,7,8-tetrahydro-5H-thieno[3,2-c]azepin-5-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0363]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0364]6-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydroquinolin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0365]6-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydroisoquinolin-2(1H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0366]6-Chloro-N-{(3S)-1-[(1S)-2-(1,3-dihydro-2H-isoindol-2-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0367]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[0368]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0369]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0370]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-thiomorpholin-4-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0371]6-Chloro-N-{(3S)-1-[(1S)-2-(2,5-dihydro-1H-pyrrol-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0372]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0373]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0374]6-Chloro-N-{(3S)-1-[(1S)-2-(3,6-dihydropyridin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0375]6-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxyquinoxalin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0376]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0377]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-pyrrole-2-carboxamide;

[0378]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-1,2,3-triazole-4-carboxamide;

[0379]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1,3-thiazole-2-carboxamide;

[0380]N1-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N2,N2-dimethylglycinamide;

[0381] Methyl3-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0382]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0383]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0384]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-4H-1,2,4-triazole-3-carboxamide;

[0385]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]pipendin-3-yl}-2-ethylbutanamide;

[0386]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino{-2-oxopyrroidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0387]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulphonamide;

[0388]5′-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0389](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0390]5-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0391]N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-3-(1H-tetraazol-5-yl)benzenesulfonamide;

[0392]4-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0393](E)-2-(4-Chlorophenyl)-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0394]5′-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0395]5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0396]5-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0397]6-Fluoro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0398]5-Chloro-3-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0399]6-Chloro-N-ethyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0400]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glydnamide;

[0401]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0402]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0403]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-}(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glydinamide;

[0404]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-}(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrroiidin-3-yl}glycinamide;

[0405]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0406]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamidehydrobromide;

[0407]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0408]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-2-(1,4-diazepan-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0409]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0410]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0411]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide;

[0412]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamideformate;

[0413]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate;

[0414]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-[(2-methyl-1,3-thiazol4-yl)methyl]naphthalene-2-suffonamideformate;

[0415]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate;

[0416]N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0417]6-Chloro-N-((3S)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0418]6-Chloro-N-((3S)-1-{(1R)-1-methyl-2-[(2S)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0419]6-Chloro-N-[(3S)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0420]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0421]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0422]6-Chloro-N-((3S)-1-{(1R)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-suffonamide;

[0423]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0424]N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0425]6-Chloro-N-[(3S)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methyinaphthalene-2-sulfonamide;

[0426]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0427]6-Chloro-N-methyl-N-((3S)-1-(1R)-1-methyl-2-[(2S)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0428]N-{(3S)-1-[(1R)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloro-N-methylnaphthalene-2-sulfonamide;

[0429]6-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0430]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(4-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0431]N-{[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-2-yl]methyl}benzamide;

[0432]6-Chloro-N-{(3S)-1-[(1R)-2-(3-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-methyinaphthalene-2-sulfonamide;

[0433]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0434]6-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0435]6-Chloro-N-methyl-N-((3R)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0436]6-Chloro-N-[(3R)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl-2-oxopyrrolidin-3-yl]-N-methyinaphthalene-2-sulfonamide;

[0437]6-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0438] EthylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0439] teft-ButylN-[(6-chloro-2-naphthyl)suffonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0440]N-[1((2R)-2-{(3R)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0441]N-{(3R)-1-[(1R)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloro-N-methylnaphthalene-2-sulfonamide;

[0442]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0443]N-Allyl-6-Chloro-N-{1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0444] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate;

[0445]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate;

[0446]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-((2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycine;

[0447]6-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0448]N-{1-[(2R)-2-((3R)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}benzamide;

[0449]N-{(3R)-1-[(1R)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0450]6-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0451]6-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0452]6-Chloro-N-((3R)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0453]6-Chloro-N-[(3R)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yonaphthalene-2-sulfonamide;

[0454]N-((3R)-1-{(1R)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;

[0455]6-Bromo-N{1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0456]6-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0457]6-Chloro-N-[(3R)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sufonamide;

[0458]N-((3R)-1-(1R)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloro-N-methyinaphthalene-2-sufonamide;

[0459]6-Chloro-N-methyl-N-((3R)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0460]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-ethoxy-2-oxopropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0461]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-methoxypropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0462]4[({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)methyl]-1-methylpyridiniumiodide;

[0463]5-(6-Amino-5-methylpyridin-3-yl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide;

[0464]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate;

[0465](E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0466]5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0467]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0468]5-Chloro-3-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0469]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0470]N2-[(6-Chloro-1-benzothien-2-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0471]5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0472]N2-[(5-Chloro-1-benzothien-2-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0473]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-phenylnaphthalene-2-sulfonamide;

[0474]6-Chloro-N-(4-fluorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0475]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-4-yinaphthalene-2-sulfonamide;

[0476]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-3-ylnaphthalene-2-sulfonamide;

[0477]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-thien-3-ylnaphthalene-2-sulfonamide;

[0478]N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0479] Benzyl(3S)-1-((2S)-2-{(3S)-3-[(2-naphthylsulfonyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-ylcarbamate;

[0480] terf-Butyl(1R,5S)-7-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate;

[0481]6-Chloro-N-((3S)-1-{(1S)-2-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0482]N1-[(1R,5S)-7-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-3-(N,N-dimethylglycyl)-3,7-diazabicyclo[3.3.1]non-2-yl]-N1-[(1S,5R)-7-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonamide;

[0483]2-{(1R,5S)-7-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-N,N,N-trimethyl-2-oxoethanaminiumchloride;

[0484]6-Chloro-N-((3S)-1-{(1S)-2-[(1R,5S)-3-(N-methylglycyl)-7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0485]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamideformate;

[0486]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{(1R,5S)-7-[2-(methylamino)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0487]6-Chloro-N-[2-(dimethylamino)ethyl]-N-[(3S)-1-((1S)-2-{(1R,5S)-7-[2-(dimethylamino)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0488]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1R,5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamidetrifluoroacetate;

[0489]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperazin-2-ylethyl]-2-oxopyrrolidin-3-yl}glycinamidetrifluoroacetate;

[0490]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamideformate;

[0491]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0492]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0493]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethynl]-2-oxopyrrolidin-3-yl}glycinamide;

[0494]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0495]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0496]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[2-(4-methylpyridin-2-yl)pyrrolidin-1-yl]-2-oxoethyl)-2-oxopyrrolidin-3-yl)glycinamide;

[0497](E)-2-(4-Chloro-3-hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0498]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulfonamideformate;

[0499]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-pyrrolidin-1-ylethyl)naphthalene-2-sulfonamideformate;

[0500]6-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;

[0501]N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1-[(1S)-1-methyl-2-morpholinyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyl]acetamide;

[0502]6-Chloro-N-{2-oxo-1-[1-(pyrrolidin-1-ylcarbonyl)propyl]pyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0503]6-Chloro-N-((3R)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0504]5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1H-indole-2-sulfonamide;

[0505]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0506]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0507]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0508]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0509]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0510]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0511]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-3-carboxamide;

[0512]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-{[(trifluoromethyl)sulfonyl]amino}piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0513]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-2-carboxamide;

[0514]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyI)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-4-carboxamide;

[0515]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0516]5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;

[0517](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholinyl-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0518](E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl)}-2-oxopyrrolidin-3-yl)ethenesulfonamide;

[0519]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholinyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0520] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0521]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;

[0522]N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0523](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0524] MethylN{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0525](E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0526]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0527]6-Chloro-N-((3S)-1-{(1S)-2-(3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0528]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;

[0529]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(1H-pyrrol-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0530]6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-dimethylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0531]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0532]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(trifluoromethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sufonamide;

[0533]6-Chloro-N-((3S)-1-(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0534]6-Chloro-N-{(3S)-1-[(1S)-2-(3-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0535]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0536]6-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0537]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-octahydroquinolin-1(2H)-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0538]6-Chloro-N-{(3S)-1-[(1S)-2-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolin-3-yl}naphthalene-2-sulfonamide;

[0539]5′-Chloro-N{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;

[0540](E)-2-(4-Chlorophenyl)-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0541]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0542]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-3-carboxamide;

[0543] Methyl4-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrroidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoate;

[0544]4-({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoicacid;

[0545]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-1,2,4-triazole-3-carboxamide;

[0546]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-2-carboxamide;

[0547]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}propanamide;

[0548]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyi)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoygpiperidin-3-yl}-1H-pyrazole-3-carboxamide;

[0549]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-ethylbutanamide;

[0550]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}cyclopentanecarboxamide;

[0551]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pentanediamide;

[0552]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyrazine-2-carboxamide;

[0553]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide;

[0554]N-{1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}malonamide;

[0555]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-methylpropanamide;

[0556]N-1-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-3-,N-3-dimethyl-beta-alaninamide;

[0557]N-}1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}succinamide;

[0558]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0559]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0560]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0561] Methyl3-({(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;p1N-1-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-,N-2-dimethylglycinamide;

[0562] Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0563]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0564]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0565]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0566] Methyl3-({(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0567]N-1-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-N-2-dimethylglycinamide;

[0568]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0569]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0570](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0571]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide(1:1);

[0572]6-Fluoro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0573]6-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0574]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamideformate;

[0575]N-{1-[(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}benzamide;

[0576]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0577]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0578]6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0579]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide;

[0580] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0581]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0582]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0583]N-{1-[(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;

[0584]6-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0585]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0586]N-[1-((2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]acetamide;

[0587]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-(3-{[(phenylsulfonyl)amino]methyl}piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0588]6-Chloro-N-((3S)-1-{(1R)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide;

[0589]6-Chloro-N-((3S)-1-{(1R)-2-[2-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide;

[0590]6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0591]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0592]N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0593] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0594]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0595]6-Chloro-N-{(3)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0596]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0597]6-Chloro-N-methyl-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0598]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methyinaphthalene-2-sulfonamide;

[0599] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0600]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0601]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-oxopyrrolidin-3-yl}glycinamide;

[0602]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0603]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0604] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate;

[0605]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0606]N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0607]6-Chloro-N-methyl-N-{(3R)-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0608]6-Chloro-N-methyl-N-((3S)-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0609]N-((3S)-1-{(1R)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloro-N-methyinaphthalene-2-sulfonamide;

[0610]6-Chloro-N-((3S)-1-{(1S)-2-[3-(ethylamino)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0611]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrrol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0612]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0613]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxybutyl)amino]piperidin-1-yl)-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0614]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin4-ylmethyl)amino]pipeidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0615]N-{(3S)-1-[(1S)-2-(3-{[(2-Aminopyrimidin-5-yl)methyl]amino}piperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0616]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolldin-3-yl]naphthalene-2-sulfonamide;

[0617]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrazol-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0618]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-4-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0619]6-Chloro-N-((3S)-1-{(1S)-2-[3-({[5-(hydroxymethyl)-2-furyl]methyl}amino)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0620]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1,3-thiazol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0621]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-{[(1-methyl-1H-imidazol-2-yl)methyl]amino}piperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0622]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0623]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(1H-imidazol-4-ylmethyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0624] Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0625]N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;

[0626]N-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;

[0627](E)-2-(5-Chlorothien-2-yl)-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0628]5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}thieno[3,2-b]pyridine-2-sulfonamide;

[0629] More preferred compounds of the invention include:

[0630]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0631]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0632]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0633]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-ylqnaphthalene-2-sulfonamide;

[0634]6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0635]6-Chloro-N-{(3S)-1-[(1S)-2-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0636]6-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0637]N-((3S)-1-{(1S)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)6-chloronaphthalene-2-sulfonamide;

[0638]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;

[0639]N-{1-[(1S)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0640]N-{(3S)-1-[(1S)-2-(2-Azabicyclo[2.2.2]oct-2-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0641]5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;

[0642](E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)ethenesulfonamideformate;

[0643]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0644]5-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0645]N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0646]N2-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0647]N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0648](E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0649](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide;

[0650] MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0651]N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0652]N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0653]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-thiomorpholin-4-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0654]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0655]N1-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N2,N2-dimethylglycinamide;

[0656] Methyl3-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0657]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0658]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0659]6-Chloro-N-ethyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0660]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0661]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0662]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0663]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0664]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0665]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide;

[0666]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamideformate;

[0667]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate;

[0668]6-Chloro-N-((3S)-1-((1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamideformate;

[0669]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl)-2-oxopyrrolidin-3-yl)-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate;

[0670]N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0671]N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0672]6-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0673] tert-ButylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholinyl-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0674]N-Allyl-6-chloro-N{1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0675]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate;

[0676]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-((3S)-1-(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycine;

[0677]6-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0678]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate;

[0679](E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0680]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;

[0681]N2-[(6-Chloro-1-benzothien-2-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0682]6-Chloro-N-((3S)-1-{(1S)-2-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0683]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{(1R,5S)-7-[2-(methylamino)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0684]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1R,5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamidetrifluoroacetate;

[0685] N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamideformate;

[0686]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0687]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0688]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0689]N2-[(6-Chloro-2-naphthyl)suffonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0690]N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0691]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulfonamideformate;

[0692]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-pyrrolidin-1-ylethyl)naphthalene-2-sulfonamideformate;

[0693]6-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;

[0694]N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1-[(1S)-1-methyl-2-morpholinyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyl]acetamide;

[0695]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0696]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0697]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0698]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0699]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0700]5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;

[0701](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0702]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0703] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0704]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;

[0705]N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0706](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0707] MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0708](E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0709]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0710]6-Chloro-N-((3S)-1-{(1S)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0711]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;

[0712]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(1H-pyrrol-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0713]6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-dimethylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0714]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0715]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-3carboxamide;

[0716] Methyl4-({1-[(2S)-2-((3S)-3-{[(6-chloro2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)4-oxobutanoate;

[0717]4-({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)4-oxobutanoicacid;

[0718]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0719]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0720]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0721] Methyl3-({(3S)-1-[(2S)-2-((3S)-3-}[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0722]N-1{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoy]piperidin-3-yl}-N-2-,N-2-dimethylglycinamide;

[0723] Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0724]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0725]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0726]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0727]6-Chloro-N-}(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0728](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0729]6-Chloro-N-}(3S)-1-[(1S)-1-methyl-2oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide(1:1);

[0730]6-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0731]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamideformate;

[0732]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0733]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0734]6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0735]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide;

[0736] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0737]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0738]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0739]6-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0740]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0741]N-[1-((2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]acetamide;

[0742]6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0743]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0744]N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0745] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0746]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0747]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0748]6-Chloro-N-methyl-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0749] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0750]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0751]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0752]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0753]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0754] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate;

[0755]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0756]N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0757]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrrol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0758]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0759]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrazol-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0760] Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0761]N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;and

[0762]N-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide.

[0763] Preferred compounds of the invention also include:

[0764]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0765]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0766]6-Chloro-N-{(3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0767]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0768]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0769]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0770]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-3-carboxamide;

[0771]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-{[(trifluoromethyl)sulfonyl]amino}piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0772]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoy]piperidine-2-carboxamide;

[0773]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-4-carboxamide;

[0774]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0775]5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;

[0776](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0777](E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)ethenesulfonamide;

[0778]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0779] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0780]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;

[0781]N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0782](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0783] MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0784](E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0785]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0786]6-Chloro-N-((3S)-1-{(1S)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0787]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;

[0788]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(1H-pyrrol-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0789]6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-dimethylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0790]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0791]6-Chloro-N-((3S)-1-}(1S)-1-methyl-2-oxo-2-[3-(trifluoromethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0792]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0793]6-Chloro-N-{(3S)-1-[(1S)-2-(3-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0794]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0795]6-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0796]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-octahydroquinolin-1(2H)-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0797]6-Chloro-N-{(3S)-1-[(1S)-2-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0798]5′-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0799](E)-2-(4-Chlorophenyl)-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0800]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0801]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-3-carboxamide;

[0802] tert-Butyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0803] Methyl4-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoate;

[0804]4-({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoicacid;

[0805]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperdin-3-yl}-1H-1,2,4-triazole-3-carboxamide;

[0806]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-2-carboxamide;

[0807]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}propanamide;

[0808]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-pyrazole-3-carboxamide;

[0809]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-ethylbutanamide;

[0810]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}cyclopentanecarboxamide;

[0811]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pentanediamide;

[0812]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyrazine-2-carboxamide;

[0813]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-pyrazole-4-carboxamide;

[0814]N-{1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}malonamide;

[0815]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-methylpropanamide;

[0816]N-1-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrroidin-1-yl)propanoyl]piperidin-3-yl}-N-3-,N-3-dimethyl-beta-alaninamide;

[0817]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}succinamide;

[0818]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0819]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0820]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0821] Methyl3-({(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0822] N-1-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-,N-2-dimethylglycinamide;

[0823] Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0824]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0825]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0826]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0827] Methyl3-({(3R)-1-[(2S)-2-((3S)-3-}[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0828]N-1-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}N-2-N-2-dimethylglycinamide;

[0829]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0830]4′-Fluoro-N-{(3S)-1-[(1S)-1-methyl-2oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1,1′-biphenyl-4-sulfonamide;

[0831]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0832](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0833]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl)-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide(1:1);

[0834]6-Fluoro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0835]6-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0836]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamideformate;

[0837]N-}1-[(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}benzamide;

[0838]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0839]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0840]6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0841]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide;

[0842] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-((3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0843]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0844]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0845]N-{1-[(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;

[0846]6-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-1-ylnaphthalene-2-sulfonamide;

[0847]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0848]N-[1-((2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]acetamide;

[0849]6-Chloro-N-methyl-N-}(3S)-1-[(1R)-1-methyl-2-oxo-2-(3-}[(phenylsulfonyl)amino]methyl}piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0850]6-Chloro-N-((3S)-1-{(1R)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide;

[0851]6-Chloro-N-((3S)-1-{(1R)-2-[2-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide;

[0852]6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0853]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0854]N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0855] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0856]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0857]1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-2-carboxylicacid;

[0858]6-Chloro-N-}(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0859]6-Chloro-N-methyl-N-}(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0860]6-Chloro-N-methyl-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0861]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sulfonamide;

[0862] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0863]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;

[0864]6-Chloro-N-(cyanomethyl)-N-}(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0865]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0866]6-Chloro-N-}(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0867]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-((3S)-1-(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0868] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate;

[0869]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0870]N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0871]6-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0872]6-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0873]N-((3S)-1-{(1R)-2-[((1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloro-N-methylnaphthalene-2-sulfonamide;

[0874]6-Chloro-N-((3S)-1-{(1S)-2-[3-(ethylamino)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0875]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrrol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0876]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0877]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxybutyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0878]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-4-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0879]N-{(3S)-1-[(1S)-2-(3-{[(2-Aminopyrimidin-5-yl)methyl]amino}piperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0880]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-2-ylmethyl)amino]piperidin-1-yl}-ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0881]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrazol-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0882]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-(3-[(pyridin-4-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0883]6-Chloro-N-((3S)-1-{(1S)-2-[3-({[5-(hydroxymethyl)-2-furyl]methyl}amino)piperdin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0884]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1,3-thiazol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0885]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3{[(1-methyl-1H-imidazol-2-yl)methyl]amino}piperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0886]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0887]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(1H-imidazolylmethyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0888] Benzyl(3S)-1-(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0889]N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;

[0890]N-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide.

[0891] More preferred compounds of the invention also include:

[0892]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0893]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0894]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0895]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0896]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0897]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0898]5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;

[0899](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0900](E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)ethenesulfonamide;

[0901]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0902] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0903]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;

[0904]N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0905](E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0906] MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0907](E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0908]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0909]6-Chloro-N-{(3S)-1-[(1S)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0910]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;

[0911]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(1H-pyrrol-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0912]6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-dimethylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0913]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;

[0914](E)-2-(4-Chlorophenyl)-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0915]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;

[0916]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-3-carboxamide;

[0917] Methyl4-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoate;

[0918]4-({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoicacid;

[0919]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-1,2,4-triazole-3-carboxamide;

[0920]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-pyrrole-2-carboxamide;

[0921]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-ethylbutanamide;

[0922]N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyrazine-2-carboxamide;

[0923]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0924]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0925]N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0926] Methyl3-({(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;

[0927]N-1-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-,N-2-dimethylglycinamide;

[0928] Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;

[0929]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;

[0930]N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;

[0931]N-{(3R)-1-[(2S)-2-((3S)-3-{[(Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;

[0932]5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0933]6-Chloro-N-{(3S)-1-((1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;

[0934](E)-2-(4Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;

[0935]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide(1:1);

[0936]6-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0937]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamideformate;

[0938]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0939]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0940]6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0941]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide;

[0942] MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0943]5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;

[0944]6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0945]6-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0946]6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0947]N-[1-((2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]acetamide;

[0948]6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0949]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0950]N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0951] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0952]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;

[0953]6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0954]6-Chloro-N-methyl-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0955]6-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sulfonamide;

[0956] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;

[0957]N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-oxopyrrolidin-3-yl}glycine;

[0958]6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0959]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinamide;

[0960]6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-N-2-oxobutyl)naphthalene-2-sulfonamide;

[0961]N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinamide;

[0962] MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate;

[0963]6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)naphthalene-2-sulfonamide;

[0964]N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;

[0965]6-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;

[0966]6-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0967]6-Chloro-N-((3S)-1-{(1S)-2-[3-(ethylamino)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;

[0968]6-Chloro-N-((3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrrol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0969]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0970]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxybutyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0971]N-{(3S)-1-[(1S)-2-(3-{[(2-Aminopyrimidin-5-yl)methyl]amino}piperidin-1-yl}-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;

[0972]6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrazol-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0973]6-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;

[0974]N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;

[0975]N-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide.

[0976] The compounds of formula (I), (Ia), (Ib), or (Ic), includingpharmaceutically acceptable derivatives thereof, are Factor Xainhibitors and as such are useful in the treatment of clinicalconditions susceptible to amelioration by administration of a Factor Xainhibitor. Such conditions include acute vascular diseases such ascoronary thrombosis (for example myocardial infarction and unstableangina), thromboembolism, acute vessel closure associated withthrombolytic therapy and percutaneous transluminal coronary angioplasty(PTCA), transient ischemic attacks, pulmonary embolism, deep veinthrombosis, peripheral arterial occlusion, prevention of vessel luminalnarrowing (restenosis), and the prevention of thromboembolic eventsassociated with atrial fibrillation, e.g. stroke; in oedema and PAFmediated inflammatory diseases such as adult respiratory shock syndrome,septic shock and reperfusion damage; the treatment of pulmonaryfibrosis; the treatment of tumour metastasis; neurogenerative diseasesuch as Parkinson's and Alzheimer's diseases; viral infection; KasabachMerritt Syndrome; Haemolytic uremic syndrome; arthritis; osteoporosis;as anti-coagulants for extracorporeal blood in for example, dialysis,blood filtration, bypass, and blood product storage; and in the coatingof invasive devices such as prostheses, artificial valves and cathetersin reducing the risk of thrombus formation.

[0977] Preferably, the condition susceptible to amelioration by a FactorXa inhibitor is selected from coronary thrombosis (for examplemyocardial infarction and unstable angina), pulmonary embolism, deepvein thrombosis and the prevention of thromboembolic events associatedwith atrial fibrillation, e.g. stroke.

[0978] Accordingly, one aspect of present invention provides a compoundof formula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptablederivative thereof for use in medical therapy, particularly for use inthe amelioration of a clinical condition in a mammal, including a human,for which a Factor Xa inhibitor is indicated.

[0979] In another aspect, the invention provides a method for thetreatment and/or prophylaxis of a mammal, including a human, sufferingfrom a condition susceptible to amelioration by a Factor Xa inhibitorwhich method comprises administering to the subject an effective amountof a compound of formula (I), (Ia), (Ib), or (Ic) or a pharmaceuticallyacceptable derivative thereof.

[0980] In another aspect, the present invention provides the use of acompound of formula (I), (Ia), (Ib), or (Ic) or a pharmaceuticallyacceptable derivative thereof, for the manufacture of a medicament forthe treatment and/or prophylaxis of a condition susceptible toamelioration by a Factor Xa inhibitor.

[0981] It will be appreciated that reference to treatment includes acutetreatment or prophylaxis as well as the alleviation of establishedsymptoms.

[0982] While it is possible that, for use in therapy, a compound of thepresent invention may be administered as the raw chemical, it ispreferable to present the active ingredient as a pharmaceuticalformulation.

[0983] In a further aspect, the invention provides a pharmaceuticalcomposition comprising at least one compound of formula (I), (Ia), (Ib),or (Ic) or a pharmaceutically acceptable derivative thereof inassociation with a pharmaceutically acceptable carrier and/or excipient.The carrier and/or excipient must be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notdeletrious to the receipient thereof.

[0984] Accordingly, the present invention further provides apharmaceutical formulation comprising at least one compound of formula(I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptable derivativethereof, thereof in association with a pharmaceutically acceptablecarrier and/or excipient. The carrier and/or excipient must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deletrious to the receipient thereof.

[0985] In another aspect, the invention provides a pharmaceuticalcomposition comprising, as active ingredient, at least one compound offormula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptablederivative thereof in association with a pharmaceutically acceptablecarrier and/or excipient for use in therapy, and in particular in thetreatment of human or animal subjects suffering from a conditionsusceptible to amelioration by a Factor Xa inhibitor.

[0986] There is further provided by the present invention a process ofpreparing a pharmaceutical composition, which process comprises mixingat least one compound of formula (I), (Ia), (Ib), or (Ic) or apharmaceutically acceptable derivative thereof, together with apharmaceutically acceptable carrier and/or excipient.

[0987] The compounds for use according to the present invention may beformulated for oral, buccal, parenteral, topical, rectal or transdermaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or the nose).

[0988] For oral administration, the pharmaceutical compositions may takethe form of, for example, tablets or capsules prepared by conventionalmeans with pharmaceutically acceptable excipients such as binding agents(e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions or they may be presented as a dryproduct for constitution with water or other suitable vehicles beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

[0989] Preparations for oral administration may be suitably formulatedto give controlled release of the active compound.

[0990] For buccal administration the compositions may take the form oftablets or lozenges formulated in a conventional manner.

[0991] The compounds according to the present invention may beformulated for parenteral administration by injection, e.g. by bolusinjection or continuous infusion. Formulations for injection may bepresented in unit dosage form, e.g. in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

[0992] The compounds according to the present invention may beformulated for topical administration by insufflation and inhalation.Examples of types of preparation for topical administration includesprays and aerosols for use in an inhaler or insufflator.

[0993] Powders for external application may be formed with the aid ofany suitable powder base, for example, lactose, talc or starch. Spraycompositions may be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as metered doseinhalers, with the use of a suitable propellant.

[0994] The compounds according to the present invention may also beformulated in rectal compositions such as suppositories or retentionenemas, e.g. containing conventional suppository bases such as cocoabutter or other glycerides.

[0995] In addition to the formulations described previously, thecompounds may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for examplesubcutaneously, transcutaneously or intramuscularly) or by intramuscularinjection. Thus, for example, the compounds according to the presentinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0996] A proposed dose of the compounds according to the presentinvention for administration to a human (of approximately 70 kg bodyweight) is 0.1 mg to 1 g, preferably to 1 mg to 500 mg of the activeingredient per unit dose, expressed as the weight of free base. The unitdose may be administered, for example, 1 to 4 times per day. The dosewill depend on the route of administration. It will be appreciated thatit may be necessary to make routine variations to the dosage dependingon the age and weight of the patient as well as the severity of thecondition to be treated. The dosage will also depend on the route ofadministration. The precise dose and route of administration willultimately be at the discretion of the attendant physician orveterinarian.

[0997] The compounds of formula (I), (Ia), (Ib), or (Ic) may also beused in combination with other therapeutic agents. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I), (Ia), (Ib), or (Ic) or a pharmaceutically acceptablederivative thereof together with a further therapeutic agent.

[0998] When a compound of formula (I), (Ia), (Ib), or (Ic) or apharmaceutically acceptable derivative thereof is used in combinationwith a second therapeutic agent active against the same disease statethe dose of each compound may differ from that when the compound is usedalone. The compounds of the present invention may be used in combinationwith other antithrombotic drugs such as thrombin inhibitors, thromboxanereceptor antagonists, prostacyclin mimetics, phosphodiesteraseinhibitors, fibrinogen antagonists, thrombolytic drugs such as tissueplaminogen activator and streptokinase, non-steroidal anti-inflammatorydrugs such as aspirin, and the like.

[0999] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined abovetogether with a pharmaceutically acceptable carrier or excipientcomprise a further aspect of the invention. The individual components ofsuch combinations may be administered either sequentially orsimultaneously in separate or combined pharmaceutical formulations byany convenient route.

[1000] When administration is sequential, either the Factor Xa inhibitoror the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

[1001] When combined In the same formulation it will be appreciated thatthe two compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

[1002] When a compound of formula (I), (Ia), (Ib), or (Ic) or apharmaceutically acceptable derivative thereof is used in combinationwith a second therapeutic agent active against the same disease statethe dose of each compound may differ from that when the compound is usedalone. Appropriate doses will be readily appreciated by those skilled inthe art. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian.

[1003] The compounds of formula (I), (Ia), (Ib), or (Ic) andphysiologically acceptable salts or solvates thereof may be prepared bythe processes described hereinafter, said processes constituting afurther aspect of the invention. In the following description, thegroups are as defined above for compounds of formula (I), (Ia), (Ib), or(Ic) unless otherwise stated.

[1004] According to a further aspect of the present invention, there isprovided a process (A) for preparing a compound of formula (I), (Ia),(Ib), or (Ic), which process comprises reacting a compound of formula(II) with a compound of formula (III).

[1005] Suitably, the reaction may be carried out in the presence of acoupling agent, for example 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole), a base, e.g.Et₃N (triethylamine), and an organic solvent, e.g. DCM(dichloromethane), suitably at room temperature.

[1006] It will be appreciated by persons skilled in the art thatcompounds of formula (I), (Ia), (Ib), or (Ic) may be prepared byinterconversion, utilising other compounds of formula (I), (Ia), (Ib),or (Ic), which are optionally protected by standard protecting groups,as precursors. For instance, compounds of formula (I) or (Ib) where R⁴and R⁵ together with the N atom to which they are bonded, form a 5-, 6-or 7-membered non-aromatic heterocyclic ring substituted by —NH₂, may beconverted into compounds of formula (I) or (Ib) possessing alternativesubstituents on the heterocyclic ring, e.g. —NHCOR^(d), —NR^(b)R^(d),—NHCOR^(e) and/or —NHC₁₋₃alkylene-R^(e), by methods well known in theart (see for example March, J., Advanced Organic Chemistry, John Wiley &Sons). Similarly, compounds of formula (Ia) where B represents—C₁₋₃alkylNH₂, may be converted into compounds of formula (Ia)possessing alternative substituents on the heterocyclic ring, e.g.—C₁₋₃alkylNH^(b)R^(c), by methods well known in the art.

[1007] Compounds of formula (II) may be prepared from compounds offormula (IV):

[1008] wherein P¹ is a suitable carboxylic acid protecting group, e.g.t-Butyl, by removal of the protecting group under standard conditions.For example, when P¹ represents t-Butyl, removal of the protecting groupmay be effected under acidic conditions, using for example TFA(trifluoroacetic acid) in a solvent such as DCM.

[1009] A compound of formula (IV) may be prepared by reacting a compoundof formula (V) with a compound of formula (VI) where P¹ is as describedabove:

 R¹—X   (VI)

[1010] Suitably, where X is a leaving group such as a halogen atom, e.g.bromine, the reaction is carried out in the presence of a base, e.g.LiHMDS (lithium hexamethyidisilylamide), potassium carbonate or sodiumcarbonate. Preferably, the reaction is effected in a suitable organicsolvent, e.g. THF, DMF, at a temperature from −78° C. to +50° C.,preferably −78° C. to +20° C.

[1011] Alternatively, where X is hydroxy, the coupling reaction iscarried out using standard reagents such as DIAD (diisopropylazodicarboxylate) and n-Bu₃P (tri n-butyl phosphine) in a solvent suchas tetrahydrofuran, suitably at room temperature:

[1012] A compound of formula (V) may be prepared by reacting a compoundof formula (VII) with a compound of formula (VII):

[1013] wherein T is a reactive group, such as a halide, preferablychloride, and P¹ is as described above. The reaction is convenientlycarried out in the presence of a base, e.g. pyridine, and in a suitablesolvent, e.g. DCM, suitably at room temperature.

[1014] A compound of formula (VII) may be prepared from a compound offormula (IX)

[1015] where P¹ is as described above and P² represents a suitable amineprotecting group, e.g. Cbz (benzyloxycarbonyl), by removal of theprotecting group under standard conditions. For example, the protectinggroup may be removed by reaction with hydrogen in the presence of ametal catalyst, e.g. palladium/charcoal at atmospheric pressure.Suitably, the reaction is carried out in an alcoholic solvent, e.g.ethanol, suitably at room temperature.

[1016] A compound of formula (IX) may be prepared from a compound offormula (X)

[1017] by cyclisation, wherein P¹ and P² are as described above and Lrepresents a leaving group, e.g. SMeRX. The ring closure may beperformed by treatment with Dowex 2×8 400 mesh OH⁻ resin in a suitablesolvent, e.g. MeCN (acetonitrile). Attentively, the ring closure may beperformed by treatment with potassium carbonate in a suitable solvent,e.g. MeCN. Generally R will represent alkyl or aralkyl and X willrepresent halide, especially iodide or sulphate.

[1018] Alternatively, a compound of formula (IX) may be prepared from acompound of formula (Xb):

[1019] where P¹ and P³ are protecting groups, by reaction with LiOH in asuitable solvent e.g. THF followed by reaction with DPPA(diphenylphosphoryl azide), a base e.g. Et₃N (triethylamine) in asuitable solvent e.g. DMF, suitably at room temperature to 70° C.

[1020] A compound of formula (Xb) may be prepared by reacting a compoundof formula (Xb-1) with a compound of formula (Xb-2)

[1021] where L¹ is a leaving group e.g. bromine, in the presence of abase e.g. Et₃N in a suitable solvent e.g. MeCN.

[1022] A compound of formula (X) in which L represents SMeRX may beformed from a compound of formula (XI)

[1023] by treatment with RX, where P¹ and P² are as described above andRX is a compound (e.g. Mel, benzyl iodide or Me₂SO₄) capable ofconverting sulphur in the SMe moiety to a sulphonium salt, in a suitablesolvent, e.g. propanone or acetonitrile.

[1024] A compound of formula (XI) may be prepared by reacting a compoundof formula (XII) with a compound of formula (XIII):

[1025] Suitably, the reaction may be carried out in the presence of acoupling agent, for example 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, HOBt, a base, e.g. Et₃N, and an organicsolvent, e.g. DCM, suitably at room temperature.

[1026] There is provided a further process (B) for preparing compoundsof formula (IV) from compounds of formula (VII). According to process(B), a compound of formula (IV) may be prepared by reductive aminationof a compound of formula (VII) with R^(1a)CHO (where R^(1a) is R¹without a CH₂ linker directly attached to the N) using a suitableselective reducing agent to produce a compound of formula (XIV),followed by reaction with a compound of formula (VIII) in the presenceof a base, e.g. pyridine, and in a solvent, e.g. DCM, suitably at roomtemperature.

[1027] The reductive amination is conveniently carried out by treatmentwith sodium triacetoxyborohydride in the presence of an acid such asacetic acid, in a solvent such as DCM, suitably at room temperature.

[1028] Compounds of formulae (III), (VI), (VIII), (Xb-1), (Xb-2), (X),(XI), (XII) and (XIII) are known compounds and/or can be prepared byprocesses well known in the art.

[1029] The various general methods described above may be useful for theintroduction of the desired groups at any stage in the stepwiseformation of the required compound, and it will be appreciated thatthese general methods can be combined in different ways in suchmulti-stage processes. The sequence of the reactions in multi-stageprocesses should of course be chosen so that the reaction conditionsused do not affect groups in the molecule which are desired in the finalproduct. For example, those skilled in the art will appreciate that,with the use of appropriate protecting groups, the coupling to any ofgroups —R¹, —SO₂R⁶ or —NR⁴R⁵ can be the final step in the preparation ofa compound of formula (I), (Ia), (Ib), or (Ic). Hence, in another aspectof the invention, the final step in the preparation of a compound offormula (I), (Ia), (Ib), or (Ic) may comprise the coupling to group —R¹by reacting a compound of formula (XV) with a compound of formula (VI):

[1030] Suitably, where X is a leaving group such as a halogen atom, e.g.bromine, the reaction is carried out in the presence of a base, e.g.LiHMDS (lithium hexamethyldisilylamide), potassium carbonate or sodiumcarbonate. Preferably, the reaction is effected in a suitable organicsolvent, e.g. THF, DMF, at a temperature from −78° C. to +50° C.,preferably −78° C. to +20° C.

[1031] In a further aspect of the present invention, the final step inthe preparation of a compound of formula (I), (Ia), (Ib), or (Ic) maycomprise the coupling to group —SO₂R⁶ by reacting a compound of formula(XVI) with a compound of formula (VIII):

[1032] The reaction is conveniently carried out in the presence of abase, e.g. pyridine, and in a suitable solvent, e.g. DCM, suitably atroom temperature.

[1033] In a further aspect of the present invention, a compound offormula (I) where R¹ is an aryl or heteroaryl group may be prepared froma compound of formula (XV) by reaction with a compound of formula(XVII):

R¹—C¹   (XVII)

[1034] where C¹ is a suitable coupling group e.g. boronate. [B(OH)₂]under metal catalysis, for example, with a copper salt such ascopper(II) acetate, in the presence of an organic solvent e.g. DCM and abase, e.g. pyridine and optionally in the presence of molecular sieves.

[1035] In a further aspect of the present invention, a compound offormula (I) where R⁶ is —SO₂—CH═CH-aryl, SO₂—CH═CH-heteroaryl,SO₂—C(CH₃)═CH-aryl or SO₂—C(CH₃)═CH-heteroaryl may be prepared from acompound of formula (XVI) where R¹ is hydrogen, by reaction with acompound of formula (XVIII), or alternatively with a compound of formula(XIX):

T¹—SO₂—C(R)═CH₂   (XVIII)

T¹—SO₂—C(R)—CH₂—T²   (XIX)

[1036] where T¹ and T² are independently reactive groups, such as ahalide, preferably chloride, in the presence of a base e.g.N,N-diisopropylethylamine and a suitable solvent e.g. MeCN, suitably atroom temperature, to provide a compound of formula (XV) where R⁶ isC(R)═CH₂, followed by reaction with a compound of formula (XX):

L-R^(h)   (XX)

[1037] Where R^(h) is aryl or heteroaryl and L is a leaving group, e.g.bromine, in the presence of a base e.g. N,N-diisopropylethylamine, and asuitable solvent e.g. dioxane and a suitable transition metal catalyste.g. di(palladium)tris(dibenzylideneacetone) and a suitable ligand e.g.2-(di-t-butylphosphino)biphenyl under an inert atmosphere e.g. nitrogen,at a temperature 20-100° C. preferably 40° C.

[1038] In a further aspect of the present invention, a compound offormula (I) where R⁶ is a biaryl group may be prepared from a compoundof formula (XVI) where R¹ is hydrogen and the amino group is optionallyprotected, for example, as a solid supported derivative derived fromreductive amination under standard conditions, by reaction with acompound of formula of formula (XXI):

[1039] wherein T is a reactive group, such as a halide, preferablychloride, and M¹ is an aryl or heteroaryl group with a suitable couplinggroup e.g. halogen, preferably bromide or iodide, in the presence of asuitable solvent e.g. DMF and a suitable base, e.g.N,N-diisopropylethylamine, followed by reaction with a compound offormula (XXII):

M²-C²   (XXII)

[1040] wherein M² is an aryl or heteroaryl group and C² is a suitablecoupling group e.g. boronate [B(OH)₂], in the presence of a metalcatalyst e.g. tetrakis(triphenylphosphine)palladium(0), a base e.g.sodium carbonate, a suitable solvent e.g. THF and optionally in thepresence of a cosolvent e.g. H₂O, followed by removal of any protectinggroups under standard conditions, e.g. under standard conditions.

[1041] Those skilled in the art will appreciate that in the preparationof the compound of formula (I), (Ia), (Ib), or (Ic) or a solvate thereofit may be necessary and/or desirable to protect one or more sensitivegroups in the molecule to prevent undesirable side reactions. Suitableprotecting groups for use according to the present invention are wellknown to those skilled in the art and may be used in a conventionalmanner. See, for example, “Protective groups in organic synthesis” by T.W. Greene and P. G. M. Wuts (John Wiley & sons 1991) or “ProtectingGroups” by P. J. Kocienski (Georg Thieme Verlag 1994). Examples ofsuitable amino protecting groups include acyl type protecting groups(e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane typeprotecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz),aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl(Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl,cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl,trityl, chlorotrityl). Examples of suitable oxygen protecting groups mayinclude for example alky silyl groups, such as trimethylsilyl ortert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl ortert-butyl; or esters such as acetate.

[1042] Various intermediate compounds used in the above-mentionedprocess, including but not limited to certain compounds of formulaeformulae (II), (IV), (V), (VII), (IX), (XIV), (XV) and (XVI) are noveland accordingly constitute a further aspect of the present invention.

[1043] The present invention will now be further illustrated by theaccompanying examples which should not be construed as limiting thescope of the invention in any way.

EXAMPLES

[1044] Abbreviations Boc t-Butyloxycarbonyl Cbz Benzyloxycarbonyl THFTetrahydrofuran DCM Dichloromethane DMF N,N-Dimethylformamide HOBT1-Hydroxybenzotriazole br broad m multiplet q quartet s singlet ttriplet d doublet

Intermediate 1 tert-ButylN-[(benzyloxy)carbonyl]-L-methionyl-L-alaninate

[1045] Z-Protected L-methionine (10 g) was dissolved in DMF (200 ml) and1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.13 g)was added followed by HOBT (5.72 g) and triethylamine (19.7 ml). Themixture was stirred for 1 h then L-alanine tert-butyl ester (7.7 g) wasadded and stirring continued for 18 h. The mixture was concentratedunder reduced pressure and partitioned between diethyl ether and water.The separated organic phase was washed with hydrochloric acid (1M),saturated sodium bicarbonate solution and brine, dried (over magnesiumsulphate) and concentrated under reduced pressure to give the titlecompound (11.9 g) as an orange oil which crystallised on standing.

[1046] Mass spectrum: Found: MH⁺411

Intermediate 2 tert-ButylN-[(benzyloxy)carbonyl]-D-methionyl-L-alaninate

[1047] Using Z-protected D-methionine, L-alanine tert-butyl ester, andthe procedure described for Intermediate 1, the title compound wasprepared.

[1048] Mass spectrum: Found: MH⁺411

Intermediate 3 (RR) tert-ButylN-[(benzyloxy)carbonyl]-D-methionyl-D-alaninate

[1049] Using Z-protected D-methionine, D-alanine tert-butyl ester andthe procedure described for Intermediate 1, the title compound wasprepared.

[1050] Mass spectrum: Found: MH⁺411

Intermediate 4 (SR) tert-ButylN-[(benzyloxy)carbonyl]-L-methionyl-D-alaninate

[1051] Using Z-protected L-methionine, D-alanine tert-butyl ester andthe procedure described for Intermediate 1, the title compound wasprepared.

[1052] Mass spectrum: Found: MH⁺411

Intermediate 5 tert-Butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1053] A solution of Intermediate 1 (11.9 g) in acetone (75 ml) wastreated with methyl iodide (18 ml) and stirred at room temperature for72 h. The reaction mixture was then concentrated under reduced pressureto give an orange solid which was dissolved in acetonitrile (200 ml).Dowex (OH⁻ form) resin (19.42 g) was added and the mixture stirred for18 h at room temperature. The mixture was filtered and the resin washedwith ethyl acetate. The filtrate was concentrated under reduced pressureto afford a yellow oil which was purified by Biotage™ chromatography(eluting with cyclohexane:ethyl acetate 3:2) to give the title compound(2.92 g) as a colourless oil.

[1054] Mass spectrum: Found: MH⁺363

Intermediate 6 tert-Butyl(2S)-2-((3R)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1055] Using Intermediate 2 and the procedure described for Intermediate5, the title compound was prepared.

[1056] Mass spectrum: Found: MH⁺363

Intermediate 7 tert-Butyl(2R)-2-((3R)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1057] Using Intermediate 3 and the procedure described for Intermediate5, the title compound was prepared.

[1058] Mass spectrum: Found: MH⁺363

Intermediate 8 tert-Butyl(2R)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1059] Using Intermediate 4 and the procedure described for Intermediate5, the title compound was prepared.

[1060] Mass spectrum: Found: MH⁺363

Intermediate 9 tert-Butyl(2S)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate

[1061] A mixture of tera-butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(2.82 g), 10% palladium on carbon (0.3 g) and ethanol (150 ml) wasstirred under an atmosphere of hydrogen for 18 h. The reaction mixturewas filtered through Harbolite™ and the filtrate was concentrated underreduced pressure to give the title compound (1.8 g) as a pale yellowoil.

[1062]¹H NMR (D₄MeOH): δ 4.56(1H, q), 3.57(1H, dd), 3.49-3.35(2H, 2×m),2.48-2.39(16H, m), 1.88-1.77(1H, m), 1.47(9H, s), 1.40 (3H, d) ppm.

Intermediate 10 tert-Butyl(2S)-2-[(3R)-3-amino-2-oxopyrrolidin-1-yl]propanoate

[1063] Using Intermediate 6 and the procedure described for Intermediate9, the title compound was prepared.

[1064]¹H NMR (D₄MeOH): δ 4.60(1H, q), 3.58(1H, dd), 3.46(1H, dt),3.41-3.33(1H, m), 2.48-2.40(1H, m), 1.82-1.70(1H, m), 1.45(9H, s),1.40(3H, d) ppm.

Intermediate 11 tert-Butyl(2R)-2-[(3R)-3-amino-2-oxopyrrolidin-1-yl]propanoate

[1065] Using Intermediate 7 and the procedure described for Intermediate9, the title compound was prepared.

[1066]¹H NMR (D₄MeOH): δ 4.58(1H, q), 3.75(1H, dd), 3.55-3.41(2H, 2×m),2.50(1H, m), 1.90(1H, m), 1.49(9H, s), 1.42(3H, d) ppm.

Intermediate 12 tert-Butyl(2R)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate

[1067] Using Intermediate 8 and the procedure described for Intermediate9, the title compound was prepared.

[1068]¹H NMR (D₄MeOH): δ 4.68(1H, q), 3.78(1H, t), 3.56-3.40(2H, 2×m),2.52(1H, m), 1.90(1H, m), 1.48(9H, s), 1.42(3H, d) ppm.

Intermediate 13(2S)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1069] tert-Butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.5 g) was dissolved in DCM (7 ml), and trifluoroacetic acid (4.7 ml)was added. The mixture was stirred at room temperature for 1.5 h andthen concentrated under reduced pressure to give the title compound(0.423 g) as a colourless oil which after azeotroping with toluene,crystallised.

[1070] Mass spectrum: Found: MH⁺307

Intermediate 14(2R)-2-((3R)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1071] Using Intermediate 7 and the procedure described for Intermediate13, the title compound was prepared.

[1072] Mass spectrum: Found: MH⁺307

Intermediate 15(2S)-2-((3R)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1073] Using Intermediate 6 and the procedure described for Intermediate13, the title compound was prepared.

[1074] Mass spectrum: Found: MH⁺307

Intermediate 16(2R)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1075] Using Intermediate 8 and the procedure described for Intermediate13, the title compound was prepared.

[1076] Mass spectrum: Found: MH⁺307

Intermediate 17 Benzyl(3S)-1-[(1S)-1-methyl-2-oxo-2-peridin-1-ylethyl]-2-oxopyrrolidin-3-ylcarbamate

[1077] To a solution of(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (3.1 g) in DCM (30 ml) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.6 g),HOBT (3.2 g) and triethylamine (2.5 ml) and the mixture was stirred atroom temperature for 5 min. Piperidine (2.9 ml) was added and theresultant mixture stirred at room temperature for 72 h. The mixture waswashed with potassium carbonate (2M), dried (over magnesium sulphate)and concentrated under reduced pressure. The residue was purified usingBiotage™ chromatography (silica, eluting with cydohexane:ethyl acetate3:1 and then ethyl acetate) to give the title compound (2.6 g) as awhite solid.

[1078] Mass spectrum: Found: MH⁺374

Intermediate 18 Benzyl(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-ylcarbamate

[1079] Using Intermediate 14 and the procedure described forIntermediate 17, the title compound was prepared.

[1080] Mass spectrum: Found: MH⁺374

Intermediate 19 Benzyl(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-ylcarbamate

[1081] Using Intermediate 15 and the procedure described forIntermediate 17, the title compound was prepared.

[1082] Mass spectrum: Found: MH⁺374

Intermediate 20 Benzyl(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-ylcarbamate

[1083] Using Intermediate 16 and the procedure described forIntermediate 17, the title compound was prepared.

[1084] Mass spectrum: Found: MH⁺374

Intermediate 21(3R)-3-Amino-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]pyrrolidin-2-one

[1085] Using Intermediate 19 and the procedure described forIntermediate 9, the title compound was prepared.

[1086] Mass spectrum: Found: MH⁺240

Intermediate 22(3R)-3-Amino-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]pyrrolidin-2-one

[1087] Using Intermediate 18 and the procedure described forIntermediate 9, the title compound was prepared.

[1088] Mass spectrum: Found: MH⁺240

Intermediate 23(3S)-3-Amino-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]pyrrolidin-2-one

[1089] Using Intermediate 17 and the procedure described forIntermediate 9, the title compound was prepared.

[1090] Mass spectrum: Found: MH⁺240

Intermediate 24(3S)-3-Amino-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]pyrrolidin-2-one

[1091] Using Intermediate 20 and the procedure described forIntermediate 9, the title compound was prepared.

[1092] Mass spectrum: Found: MH⁺240

[1093] Intermediate 25

tert-Butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1094] A solution of tert-butyl(2S)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate (1.8 g) in DCM (75ml) was treated with 6-chloronaphthylsulphonyl chloride¹ (2.28 g) andpyridine (0.705 ml) and stirred at room temperature for 72 h. Themixture was washed with water and concentrated under reduced pressure toyield an oil which was purified by Biotage™ chromatography (eluting withcyclohexane:ethyl acetate 3:1) to give the title compound (2.31 g), as awhite solid.

[1095] Mass spectrum: Found: MH⁺453

Intermediate 26 tert-Butyl(2S)-2-((3R)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1096] Using Intermediate 10 and the procedure described forIntermediate 25, the title compound was prepared.

[1097]¹H NMR (CDCl₃): δ 8.45(1H, br.s), 7.96-7.83(4H, m), 7.56 (1H, dd),5.41(1H, br.s), 4.66 (1H, q), 3.73(1H, dt), 3.42-3.34(2H, m), 2.62(1H,m), 2.01(1H, m), 1.38-1.32(12H, s+d) ppm.

Intermediate 27 tert-Butyl(2R)-2-((3R)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1098] Using Intermediate 11 and the procedure described forIntermediate 25, the title compound was prepared.

[1099] Mass spectrum: Found: MH⁺453

Intermediate 28 tert-Butyl(2S)-2-{(3R)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino[-2-oxopyrrolidin-1-yl}propanoate

[1100] Using Intermediate 26 and methyl tosylate, and the proceduredescribed for Intermediate 52, the title compound was prepared.

[1101] Mass spectrum: Found: MH⁺467

Intermediate 29(2S)-2-((3S)-3-}[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1102] tert-Butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.643 g) was dissolved in DCM (19 ml), and trifluoroacetic acid (19 ml)was added. The mixture was stirred at room temperature for 2.5 h andthen concentrated under reduced pressure. Anhydrous DCM (4 ml) was addedand the solution concentrated under reduced pressure. Repetitiveaddition of DCM and concentration under reduced pressure provided thetitle compound (0.56 g) as a white foam.

[1103] Mass spectrum: Found: MH⁺397

Intermediate 30(2S)-2-{(3R)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid

[1104] Using Intermediate 28 and the procedure described forIntermediate 29, the title compound was prepared.

[1105] Mass spectrum: Found: MH⁺411

Intermediate 31(2S)-2-((3R)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1106] Using Intermediate 26 and the procedure described forIntermediate 29, the title compound was prepared.

[1107] Mass spectrum: Found: MH⁺397

Intermediate 32(2R)-2-((3R)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1108] Using Intermediate 27 and the procedure described forIntermediate 29, the title compound was prepared.

[1109] Mass spectrum: Found: MH⁺397

Intermediate 33 tert-Butyl(2R)-2-(3-azido-2-oxopyrrolidin-1-yl)propanoate

[1110] To a solution of D-alanine tert-butylester (1.28 g) andN,N-diisopropylethyamine (1.22 ml) in acetonitrile (15 ml), was added asolution of ethyl 2-azido-4-bromobutanoate (1 g) and sodium iodide (0.02g) in acetonitrile (5 ml). The mixture was heated at 60° C. for 60 h andthen concentrated under pressure to give a brown oil. This oil waspartitioned between DCM and water. The separated organic layer waswashed further with water and dried (over magnesium sulphate), andconcentrated under reduced pressure. The residual brown oil was purifiedusing Biotage™ chromatography (silica, eluting with cyclohexane;ethylacetate 3:1) to give the title compound (0.204 g) as a mixture of twodiastereoisomers.

[1111] T.l.c. (cyclohexane:ethyl acetate, 2:1) R_(f) 0.20

Intermediate 34 tert-Butyl(2S)-2-(3-azido-2-oxopyrrolidin-1-yl)propanoate

[1112] Using ethyl 2-azido-4-iodobutanoate and L-alanine tert-butylester, and the procedure described for Intermediate 33, the titlecompound was prepared as a mixture of two diastereoisomers.

[1113] T.l.c. (cyclohexane:ethyl acetate, 3:1) R_(f) 0.15

Intermediate 35 tert-Butyl(2R)-2-(3-{[(6chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1114] A mixture of tert-butyl(2R)-2-(3-azido-2-oxopyrrolidin-1-yl)propanoate (0.035 g), 10% palladiumon carbon (0.003 g) and ethanol (2 ml) was stirred under an atmosphereof hydrogen for 16 h. The reaction mixture was filtered throughHarbolite™ and the filtrate was concentrated under reduced pressure togive a yellow gum. The gum (0.026 g) in DCM (2 ml) was treated with6-chloronaphthylsulphonyl chloride¹ (0.03 g) and pyridine (0.02 ml) andstirred at room temperature for 42 h. The mixture was washed with waterand concentrated under reduced pressure to yield an oil which waspartially purified using SPE (aminopropyl, eluting with methanol). Theorganic washings were concentrated under reduced pressure and theresidue dissolved in DCM. The organic solution was purified by SPE(aminopropyl, eluting with methanol containing 10% v/v 2N HCl) to givethe title compound (0.012 g) as a white solid.

[1115] Mass spectrum: Found: MH⁺453

Intermediate 36 tert-Butyl(2S)-2-(3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1116] Using Intermediate 34 and the synthetic procedure described forIntermediate 35, the title compound was prepared.

[1117] Mass spectrum: Found: MH⁺453

Intermediate 37(2R)-2-(3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1118] Using Intermediate 35, and the synthetic procedure forIntermediate 13, the title compound was prepared.

[1119] Mass spectrum: Found: MH⁺411

Intermediate 38(2S)-2-(3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1120] Using Intermediate 36, and the synthetic procedure forIntermediate 13, the title compound was prepared.

[1121] Mass spectrum: Found: MH⁺411

Intermediate 39(2R)-2-(3-{[(3′-Chloro-1,1′-biphenyl-4-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1122] Using Intermediate 33 and (3′-chloro-1,1′-biphenyl-4-yl)sulfonylchloride and similar chemistry to that described for Intermediates 35and 37, the title compound was prepared.

[1123] Mass spectrum: Found: MH⁺424

Intermediate 40(2R)-2-(3-{[(3-Chloroisoquinolin-7-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1124] Using Intermediate 33 and (3-chloroisoquinolin-7-yl)sulfonylchloride and similar chemistry to that described for Intermediates 35and 37, the title compound was prepared.

[1125] Mass spectrum: Found: MH⁺398

Intermediates 41* and 42tert-Butyl(2R)-2-((3R)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(1)tert-Butyl(2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(2)

[1126] A mixture of tert-butyl(2R)-2-(3-azido-2-oxopyrrolidin-1-yl)propanoate (0.204 g), 10% palladiumon carbon (0.02 g) and ethanol (10 ml) was stirred under an atmosphereof hydrogen for 5 h. The reaction mixture was filtered throughHarbolite™ and the filtrate was concentrated under reduced pressure togive a yellow oil. The oil (0.150 g) in DCM (10 ml) was treated with6-chloronaphthylsulphonyl chloride¹ (0.188 g) and pyridine (0.058 ml)and stirred at room temperature for 72 h. The mixture was washed withwater and concentrated under reduced pressure to yield an oil which waspurified by Biotage™ chromatography (eluting with cyclohexane:ethylacetate 2:1) to give the title compounds [(1)—0.067 g and (2)—0.060 g],both as white solids.

[1127] (1) Mass spectrum: Found: MH⁺453 (2) Mass spectrum: Found: MH⁺453

[1128] Using Intermediates 41 and 42 and the synthetic proceduredescribed for Intermediate 52, the following compounds were similarlyprepared:

Intermediate 43tert-Butyl(2R)-2-((3R)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1129] Mass spectrum: Found: MH⁺467

Intermediate 44tert-Butyl(2R)-2-(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1130] Mass spectrum: Found: MH⁺467

Intermediate 45 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1131] A solution of tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.07 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treatedwith lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.186 ml),followed by 1-bromo-2-butanone (0.08 ml). The resultant solution wasallowed to reach room temperature and stirred for a further 72 h.Methanol (1 ml) was added and the resultant solution concentrated underreduced pressure. The residue was purified using SPE (silica, elutingwith cyclohexane:ethyl acetate 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5,ethyl acetate and methanol:ethyl acetate 1:9) to give the title compound(0.07 g) as a gum.

[1132] Mass spectrum: Found: MH⁺523 Similarly prepared using othercommercially available alkyl halides, were:

Intermediate 46 tert-Butyl(2S)-2-((3S)-3-}(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1133] Mass spectrum: Found: MH⁺510

Intermediate 47 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-methoxy-2-oxoethyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1134] Mass spectrum: Found: MH⁺525

Intermediate 48(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid

[1135] tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate(0.07 g) was dissolved in DCM (2 ml), and trifluoroacetic acid (2 ml)was added. The mixture was stirred at room temperature for 1.5 h andthen partitioned between water and DCM. The organic layer was separated,dried (over magnesium sulphate) and concentrated under reduced pressureto give the title compound (0.063 g) as an orange gum.

[1136] Mass spectrum: Found: MH⁺467 Using similar chemistry, thefollowing were prepared:

Intermediate 49(2S)-2-{(3S)-3-((2-Amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1137] Using Intermediate 46 and similar chemistry to that described forIntermediate 48, the title compound was prepared.

[1138] Mass spectrum: Found: MH⁺454

Intermediate 50(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](2-methoxy-2-oxoethyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid

[1139] Using Intermediate 47 and similar chemistry to that described forIntermediate 48, the title compound was prepared.

[1140] Mass spectrum: Found: MH⁺469

Intermediate 517-[({(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}amino)sulfonyl]-2-naphthylbenzoate

[1141] The title compound was prepared using Intermediate 23,7-(chlorosulfonyl)-2-naphthyl benzoate, and the synthetic proceduredescribed for Intermediate 25.

[1142] Mass spectrum: Found: MH⁺446

Intermediate 52 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1143] A solution of tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.1 g) in THF (5 ml) was cooled to −78° C. under nitrogen, and treatedwith lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.23 ml),followed by methyl tosylate (0.206 g). The resultant solution wasallowed to reach room temperature and stirred for a further 16 h. Themixture was quenched with sodium acetate (0.074 g), stirred for 1 h andpartitioned between water and ethyl acetate. The separated organic layerwas washed with water, dried (over magnesium sulphate), and concentratedunder reduced pressure. The residue was purified using SPE (silica,eluting with cyclohexane:ethyl acetate 10:1, 8:1, 5:1, 3:1, 2:1,1:1) togive the title compound (0.101 g) as a colourless gum.

[1144] Mass spectrum: Found: MH⁺467

Intermediate 53(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid

[1145] tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate(0.1 g) was dissolved in DCM (2 ml), and trifluoroacetic acid (2 ml) wasadded. The mixture was stirred at room temperature for 1.5 h and thenpartitioned between water and DCM. The organic layer was separated,dried (over magnesium sulphate) and concentrated under reduced pressureto give the title compound (0.09 g) as an colourless gum.

[1146] Mass spectrum: Found: MH⁺411

Intermediate 54(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino]-2-oxopyrrolidin-1-yl)propanoicacid

[1147] Using Intermediate 42 and the procedure described forIntermediate 53, the title compound was similarly prepared.

[1148] Mass spectrum: Found: MH⁺397

Intermediate 55(2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid

[1149] Using Intermediate 44 and the procedure described forIntermediate 53, the title compound was similarly prepared.

[1150] Mass spectrum: Found: MH⁺411

Intermediate 56(2R)-2-{(3R)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid

[1151] Using Intermediate 43 and the procedure described forIntermediate 53, the title compound was similarly prepared.

[1152] Mass spectrum: Found: MH⁺411

Intermediate 57 5-Chlorothieno[2,3-b]pyridine-2-sulfonyl Chloride

[1153] n-Butyl lithium (1.6M in hexanes, 0.37 ml) was added to a cooled(−78° C.) solution of 5-chlorothieno[2,3-b]pyridine* (0.100 g) inanhydrous THF (5 ml) over 15 min. The reaction was stirred for a further5 min, warmed to −45° C. and stirred for 40 min. The mixture was cooledto −70° C. and sulphur dioxide gas was bubbled into the vessel over 10min. The reaction was allowed to reach room temperature over 45 min, andthen concentrated under reduced pressure. The residue was dissolved inanhydrous DCM (5 ml), treated with N-chlorosuccinimide (0.097 g) andstirred at room temperature for 75 min. The solution was filtered, andthe filtrate concentrated under reduced pressure to give the titlecompound (0.198 g) as a yellow solid.

[1154] Mass Spectrum: Found: MH⁺277 for dimethylamine quenched massspectrum sample

Intermediate 58 tert-Butyl 3-(benzoylamino)piperidine-1-carboxylate

[1155] A solution of benzoic add (0.123 g) in DMF (5 ml) was treatedwith 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.231 g), HOBT (0.163 g) and triethylamine (0.56 ml) and stirred atroom temperature for 1 h. A solution of 3-amino-1-N-Boc-piperidine (0.3g) in DMF (1 ml) was then added and stirring continued for 18 h. Thesolution was concentrated under reduced pressure to give an oil whichwas partitioned between ethyl acetate and water. The separated organicextracts were washed with water, hydrochloric acid (2N), saturatedsodium bicarbonate solution and brine, dried (over magnesium sulphate)and concentrated under reduced pressure to give the title compound(0.120 g) as a yellow solid.

[1156] Mass spectrum: Found: MH⁺305

Intermediate 59 N-Piperidin-3-ylbenzamide

[1157] A solution of tert-butyl 3-(benzoylamino)piperidine-1-carboxylate(0.120 g) in DCM (5 ml) was treated with trifluoroacetic acid (5 ml) andstirred at room temperature for 6 h. The mixture was concentrated underreduced pressure to give a yellow oil which following neutralisationwith aqueous ammonia solution, was purified using SPE (silica, elutingwith methanol and 5% aqueous ammonia in methanol) to give the titlecompound (0.085 g) as an off-white solid.

[1158]¹H NMR (D₄MeOH): δ 7.82(2H, br.d), 7.53(1H, tt), 7.45(2H, t),4.27(1H, tt), 3.50(1H, br.dd), 3.34(1H, br.dt), 2.96(2H, m), 2.08(2H,m), 1.90-1.68(2H, m) ppm.

Intermediate 60 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-furylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1159] A solution of tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.07 g) in THF (0.5 ml) was treated with diisopropyl azodicarboxylate(0.06 ml), 3-furfuryl alcohol (0.030 g) and tributylphosphine (0.075 ml)and shaken at room temperature for 18 h. The mixture was concentratedunder reduced pressure and the residue purified by Biotage™chromatography (eluting with cyclohexane:ethyl acetate 3:1) to give thetitle compound (0.015 g) as a colourless gum.

[1160] Mass spectrum: Found: MH⁺533 Using similar chemistry, thefollowing was prepared:

Intermediate 61 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](1,3-thiazol-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1161] Mass spectrum: Found: MH⁺550

Intermediate 62(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](1,3-thiazol-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl)propanoicacid

[1162] A solution of tert-butyl(2S)-2-{(3S)-3-[[(6-chloro2-naphthyl)sulfonyl](1,3-thiazol-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate(0.03 g) in DCM (1 ml) was treated with trifluoroacetic acid (1 ml) andstirred at room temperature for 1 h. The solution was then concentratedunder reduced pressure to give the title compound (0.019 g) as acolourless solid.

[1163] Mass spectrum: Found: MH⁺494 Using Intermediate 60 and similarchemistry to that described for Intermediate 62, the following wasprepared:

Intermediate 63(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](2-furylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid Mixture with(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (56:44)

[1164] Mass spectrum: Found: MH⁺478

Intermediate 64 tert-Butyl5-chloro-2-[({(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)sulfonyl]-1H-indole-1-carboxylate

[1165] 1-tert-Butoxycarbonyl-5-chloroindole (0.1 g) was dissolved inanhydrous THF (2 ml) under nitrogen and cooled to −78° C. n-Butyllithium(1.6M in hexanes, 0.273 ml) was added dropwise over 10 min. Afterstirring at −78° C. for 45 min, sulphur dioxide gas was bubbled throughthe reaction for 5 min. The reaction mixture was allowed to reach roomtemperature over 2 h and concentrated under reduced pressure to give anoff-white solid. The solid was re-suspended in anhydrous DCM (2 ml) andtreated with N-chlorosuccinimide (0.0584 g). The mixture was thenstirred for 1 h at room temperature and any remaining white solidremoved by filtration. Half of this filtrate was treated with pyridine(0.017 ml) and Intermediate 87 (0.022 g). The reaction mixture wasstirred at 40° C. for 5 h and then 72 h at 30° C. in a sealed vessel.The reaction mixture was washed with water, the organic phase separatedand dried (over magnesium sulphate), and concentrated under a stream ofnitrogen to give a residue which was purified by mass directedpreparative h. p.l.c. to give the title compound (0.011 g) as acolourless glass.

[1166] Mass spectrum: Found: MH⁺555

Intermediate 65N-{(3S)-1-[(1S)-1-Methyl-2-morpholin-4-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1167] 2-Chloroethanesulfonyl chloride (0.284 ml) was added dropwise toa mixture of Intermediate 87 (0.436 g) and N,N-di-isopropylethylamine(0.938 ml) in dry acetonitrile (6 ml) at 0° C. over 2 min. The mixturewas allowed to reach room temperature and stirred for 3 days, afterwhich the reaction was quenched with water and concentrated underreduced pressure to give a brown residue. This residue was partitionedbetween ethyl acetate and water. The combined organic extracts weredried (over magnesium sulphate) and concentrated under reduced pressureto give a brown foam which was purified by SPE (silica, eluting withethyl acetate:cyclohexane 1:1, ethyl acetate and then ethylacetate:methanol 19:1) to give the title compound (0.227 g) as a clearfilm.

[1168] Mass Spectrum: Found: MH⁺332

Intermediate 66(3S)-3-{[(6-Chloro-1,3-benzothiazol-2-yl)thio]amino}-1-[(1S)-1-methyl-2-morpholin-4-2-oxoethyl]pyrrolidin-2-one

[1169] N-Chlorosuccinimide (0.37 g) was added to4-chloro-2-mercaptobenzothiazole (0.5 g) in DCM (15 ml) under nitrogen,and stirred at room temperature for 3 h. A solution of Intermediate 87(0.569 g) and triethylamine (1.04 ml) in anhydrous DCM (5 ml) were addedand the resulting mixture stirred at room temperature under nitrogen for2 h. The solution was filtered and the filtrate was diluted with DCM.The organic solution was washed with water and brine, dried (overmagnesium sulphate) and concentrated under reduced pressure. The residuewas purified by SPE (silica, eluting with cyclohexane: ethyl acetate 1:1increasing polarity to ethyl acetate:methanol 19:1) to give the titlecompound (0.3 g) as a white solid.

[1170] Mass spectrum: Found: MH⁺441

Intermediate 67 tert-Butyl(2S)-2-((3S)-3-{[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1171] A solution of tert-butyl(2S)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate (0.337 g) inacetonitrile (20 ml) was treated with triethylamine (0.41 ml) and5′-chloro-2,2′-bithiophene-5-sulfonyl chloride² (0.372 g) and stirred atroom temperature for 17 h. The mixture was concentrated under reducedpressure and the residue purified using SPE (aminopropyl, eluting withmethanol) to give the title compound (0.651 g) as a brown oil.

[1172] Mass spectrum: Found: MH⁺491 Using similar chemistry andIntermediate 9, the following were prepared:

Intermediate 68 teat-Butyl(2S)-2-[(3S)-3-({[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]propanoate

[1173] Mass spectrum: Found: MH⁺429

Intermediate 69 tert-Butyl(2S)-2-((3S)-3-{[(6-chloro-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1174] Mass spectrum: Found: MH⁺459

Intermediate 70 tert-Butyl(2S)-2-((3S)-3-{[(5-chloro-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1175] Mass spectrum: Found: MH⁺459

Intermediate 71 tert-Butyl(2S)-2-{(3S)-3-[[(5′-chloro-2,2′-bithien-5-yl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1176] Using Intermediate 67, and the synthetic procedure described forIntermediate 45, the title compound was similarly prepared.

[1177] Mass spectrum: Found: MH⁺561

Intermediate 72 tert-Butyl(2S)-2-{(3S)-3-[{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}(2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1178] Using Intermediate 68, and the synthetic procedure described forIntermediate 45, the title compound was similarly prepared.

[1179] Mass spectrum: Found: MH⁺499

Intermediate 73 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-1-benzothien-2-yl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1180] Using Intermediate 69, and the synthetic procedure described forIntermediate 45, the title compound was similarly prepared.

[1181] Mass spectrum: Found: MH⁺529

Intermediate 74 tert-Butyl(2S)-2-{(3S)-3-[[(5-chloro-1-benzothien-2-yl)sulfonynl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1182] Using Intermediate 70, and the synthetic procedure described forIntermediate 45, the title compound was similarly prepared.

[1183] Mass spectrum: Found: MH⁺529

Intermediate 75 tert-Butyl(2S)-2-[(3S)-3-{(2-amino-2-oxoethyl)[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]propanoate

[1184] Using Intermediate 68, and the synthetic procedure described forIntermediate 45, the title compound was similarly prepared.

[1185] Mass spectrum: Found: MH⁺487

Intermediate 76 tert-Butyl(2S)-2-((3S)-3-{(2-amino-2-oxoethyl){[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1186] Using Intermediate 67, and the synthetic procedure described forIntermediate 45, the title compound was similarly prepared.

[1187] Mass spectrum: Found: MH⁺548

Intermediate 77 Dimethyl(2R)-2-{[(benzyloxy)carbonyl]aminol}pentanedioate

[1188] Thionyl chloride (30 ml) was added to a cooled solution ofD-glutamic acid (33.2 g) in methanol (250 ml) and the mixturesubsequently heated under reflux for 16 h. On cooling, the mixture wasconcentrated under reduced pressure and the residue azeotroped withtoluene to give a white solid. This was stirred with ethyl acetate,water and potassium hydrogen carbonate at 0° C. while benzylchloroformate (30 ml) was added. The mixture was warmed to roomtemperature and stirred for 5 h. The separated organic phase was washedwith water, dried (over magnesium sulphate) and concentrated underreduced pressure to provide a yellow oil. This oil was purified usingflash column chromatography (silica, eluting with cyclohexane:ethylacetate 2:1) to give the title compound (22.45 g) as an oil.

[1189]¹H NMR (CDCl₃): δ 7.40-7.30(5H, m), 5.50(1H, br.d), 5.10(2H, s),4.40(1H, m), 3.73(3H, s), 3.64(3H, s), 2.50-2.35(2H, m), 2.30-1.90(2H,2×m) ppm.

Intermediate 78 Benzyl (1S)-4-hydroxy-1-(hydroxymethyl)butylcarbamate

[1190] A solution of Z-glutamic acid (10 g) in THF (50 ml) was addedportionwise to a stirred solution of lithium aluminium hydride in THF(1M, 100 ml) under nitrogen at 0° C., and the resultant mixture stirredat room temperature for 24 h. Wet ether was added and the mixture wasdiluted with water and ethyl acetate. The mixture was filtered throughHarbolite™ and the filtrate diluted further with water. The separatedorganic phase was washed with water, dried (over magnesium sulphate) andconcentrated under reduced pressure to give solid which was purified byflash column chromatography (silica, eluting with ethyl acetate) to givethe title compound (2.74 g) as a white solid.

[1191]¹H NMR (D₆DMSO): δ 7.40-7.30(5H, m), 6.95(1H, br.d), 5.00(2H, s),4.65(1H, br.t), 4.40(1H, br.t), 3.50-3.20(5H, m), 1.65-1.15(4H, m) ppm.

Intermediate 79 Benzyl (1R)-4-hydroxy-1-(hydroxymethyl)butylcarbamate

[1192] A solution of dimethyl(2R)-2-{[((benzyloxy)carbonyl]amino}pentanedioate (22.4 g) in dry THF(74 ml) was added dropwise over 1 h to a stirred mixture of lithiumborohydride (4.5 g) in THF (200 ml) at room temperature, under nitrogen.Stirring at room temperature was continued for 3 days. The reactionmixture was diluted with brine and water, and extracted with ethylacetate. The combined organic extracts were washed with brine, dried(over magnesium sulphate) and concentrated under reduced pressure togive the title compound (16.5 g) as a white solid.

[1193]¹H NMR (D₆DMSO): δ 7.41-7.30(5H, m), 7.00(1H, br.d), 5.02(2H, s),4.65(1H, br.t), 4.40(1H, br.t), 3.50-3.20(5H, m), 1.63-1.20(4H, m) ppm.

Intermediate 80(2R)-2-{[(Benzyloxy)carbonyl]amino}-5-[(methylsulfonyl)oxy]pentylmethanesulfonate

[1194] A solution of benzyl(1R)-4-hydroxy-1-(hydroxymethyl)butylcarbamate (1.5 g) in DCM (60 ml)was treated with triethylamine (3.3 ml) and stirred at room temperaturefor 10 min. Methanesulphonyl chloride (1.34 ml) was then added dropwiseand the resultant mixture stirred at 0° C. for 75 min. Sodiumbicarbonate solution was added and the reaction mixture allowed to reachroom temperature over 1 h. The organic layer was separated, washed withbrine, dried (over magnesium sulphate) and concentrated under reducedpressure to give a yellow oil. The oil was purified using Biotage™chromatography (eluting with hexane:ethyl acetate 1:2, 1:3) to give thetitle compound (1.924 g) as a yellow oil

[1195] Mass spectrum: Found: MH⁺410 Similarly prepared usingIntermediate 80 was:

Intermediate 81(2S)-2-{[(Benzyloxy)carbonyl]amino}-5-[(methylsulfonyl)oxy]pentylmethanesulfonate

[1196] Mass spectrum: Found: MH⁺410

Intermediate 82 Benzyl (3R)-piperidin-3-ylcarbamate

[1197] Liquid ammonia (ca. 30 ml) was added to a solution of(2R)-2-{[(benzyloxy)carbonyl]amino}-5-[(methylsulfonyl)oxy]pentylmethanesulfonate (1 g) in THF (15 ml) at −78° C. in a bomb reactionvessel and then the resultant mixture was allowed to reach roomtemperature. After 46 h, the solution was concentrated under reducedpressure to give an off-white solid which was purified using SPE(silica, eluting with methanol, methanol:aqueous ammonia 95:5, 9:1) togive the title compound (0.587 g) as an off white solid.

[1198] Mass spectrum: Found: MH⁺235 Similarly prepared usingIntermediate 81 was:

Intermediate 83 Benzyl (3S)-piperidin-3-ylcarbamate

[1199] Mass spectrum: Found: MH⁺235

Intermediate 84 Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate

[1200] A solution of(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (0.408 g) in DCM (21 ml) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.394 g),HOBT (0.278 g) and triethylamine (0.286 ml) and stirred at roomtemperature for 1 h. A solution of benzyl (3S)-piperidin-3-ylcarbamate(0.361 g) in DCM (1 ml) was then added and stirring continued for 72 h.The mixture was partitioned between DCM and water. The separated organicextracts were washed with water and brine, dried (over magnesiumsulphate), and concentrated under reduced pressure. The residue waspurified using Biotage™ chromatography (eluting with hexane:ethylacetate 1:7→1:10) to give the title compound (0.268 g) as an oil.

[1201] Mass spectrum: Found: MH⁺614

Intermediate 85 Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate

[1202] Using benzyl (3R)-piperidin-3-ylcarbamate and the proceduredescribed for Intermediate 84, the title compound was prepared.

[1203] Mass spectrum: Found: MH⁺614

Intermediate 86 Benzyl(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-ylcarbamate

[1204](2S)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (84.5 g) was dissolved in DMF (21) andO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 g) was added, followed by N,N-diisopropylethylamine (92 ml) andmorpholine (46 ml). The mixture was stirred under nitrogen for 2.5 h,and saturated aqueous ammonium chloride was added. The mixture wasstirred for 15 min then partitioned between water and ethyl acetate. Theseparated organic phase was washed with lithium chloride (10% byweight), followed by saturated sodium bicarbonate and brine. The organiclayer was dried (over sodium sulphate) and concentrated under reducedpressure to give the title compound (65 g) as a yellow solid.

[1205] Mass spectrum: Found: MH⁺376

Intermediate 87(3S)-3-Amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one

[1206] A mixture of benzyl(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-ylcarbamate(20 g), 10% palladium on carbon (2 g) and ethanol (1.3 l) was stirredunder an atmosphere of hydrogen for 16 h. The reaction mixture wasfiltered through Celite™ and the filtrate was concentrated under reducedpressure to give the title compound (12.3 g) as a pale white oil.

[1207]¹H NMR (D₄MeOH): δ 5.05(1H, dd), 3.59(9H, m), 3.37(2H, m),2.42(1H, m), 1.75(1H, m), 1.30(3H, d) ppm.

Intermediate 886-Chloro-N-((3S)-1-{(1S)-2-[(1R,5S)-3-(tert-butyloxycarbonyl)-7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1208] Using Example 408 and N-Boc-sarcosine, and the syntheticprocedure described for Example 409, the title compound was prepared.

[1209] Mass spectrum: Found: MH⁺676

Intermediate 89 tert-Butyl(2S)-2-((3S)-3-{[(2-methyl-1,3-thiazolyl)methyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1210] A solution of 2-methyl-1,3-thiazole4-carbaldehyde (0.028 g) inDCM (2 ml) was treated with Intermediate 9 (0.05 g) followed by aceticacid (0.013 ml) and tetramethylammonium triacetoxyborohydride (0.116 g),and the resultant mixture stirred at room temperature for 66 h. Thereaction mixture was partitioned between water and DCM. The organiclayer was separated, dried (over magnesium sulphate) and concentratedunder reduced pressure to give the title compound (0.07 g) as an oil.

[1211] Mass spectrum: Found: MH⁺340 Using similar chemistry, thefollowing were prepared:

Intermediate 90 tert-Butyl(2S)-2-{(3S)-2-oxo-3-[(pyridin-4-ylmethyl)amino]pyrrolidin-1-yl}propanoate

[1212] Mass spectrum: Found: MH⁺320

Intermediate 91 tert-Butyl(2S)-2-{(3S)-2-oxo-3-[(pyridin-2-ylmethyl)amino]pyrrolidin-1-yl}propanoate

[1213] Mass spectrum: Found: MH⁺320

Intermediate 92 tert-Butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl][(2-methyl-1,3-thiazol-4-yl)methyl]amino}-2-oxopyrrolidin-1-yl)propanoate

[1214] Using Intermediate 89 and the synthetic procedure described forIntermediate 25, the title compound was similarly prepared.

[1215] Mass spectrum: Found: MH⁺564

Intermediate 93 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](pyridin-4-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1216] Using Intermediate 90 and the synthetic procedure described forIntermediate 25, the title compound was similarly prepared.

[1217] Mass spectrum: Found: MH⁺544

Intermediate 94 tert-Butyl(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](pyridin-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate

[1218] Using Intermediate 91 and the synthetic procedure described forIntermediate 25, the title compound was similarly prepared.

[1219] Mass spectrum: Found: MH⁺544

Intermediate 95(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl][(2-methyl-1,3-thiazol-4-yl)methyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1220] Using Intermediate 92 and the synthetic procedure described forIntermediate 13, the title compound was similarly prepared.

[1221] Mass spectrum: Found: MH⁺508

Intermediate 96(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](pyridin-4-ylmethyl)amino}-2-oxopyrrolidin-1-yl}propanoicacid hydrochloride

[1222] Using Intermediate 93 and the synthetic procedure described forIntermediate 13, the title compound was similarly prepared.

[1223] Mass spectrum: Found: MH⁺488

Intermediate 97(2S)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](pyridin-2-ylmethyl)amino}-2-oxopyrrolidin-1-yl}propanoicacid hydrochloride

[1224] Using Intermediate 94 and the synthetic procedure described forIntermediate 13, the title compound was similarly prepared.

[1225] Mass spectrum: Found: MH⁺488

Intermediate 98(3S)-3-{[2-Methoxy-4-(2-polystyrylethoxy)benzyl]amino}-1-[(1S)-1-methyl-2-oxo-2-(1-piperidinyl)ethyl]-2-pyrrolidinone

[1226] A solution of(3S)-3-amino-1-[(1S)-1-methyl-2-oxo-2-(1-piperidinyl)ethyl]-2-pyrrolidine(0.795 g) in anhydrous DMF (ca. 8 ml) was added to pre-swollen2-(3-methoxy-4-formylphenoxy)ethoxymethyl polystryene resin (1.45 g)followed by the N,N-diisopropylethylamine (0.58 ml) and acetic acid(0.19 ml). The mixture was shaken at room temperature for 2 h, afterwhich time a solution of tetra n-butylammonium borohydride (0.856 g) andacetic acid (0.19 ml) in anhydrous DMF (ca. 5 ml) was added. The mixturewas shaken for 20 h at room temperature, filtered and washed with DMF,10% ethanolamine in DMF, DMF, DCM, methanol and diethyl ether. Theresultant resin was dried in vacuo to give the title compound (1.53 g)as pale yellow beads.

[1227] IR: v_(max) 2890, 2327, 2282, 1749, 1715 and 1643 cm⁻¹

Intermediate 995-Bromo-N-[2-methoxy-4-(2-polystyrylethoxy)benzyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(1-piperidinyl)ethyl]-2-oxopyrrolidinyl}-2-thiophenesulfonamide

[1228] Intermediate 98 pre-swollen with DCM (ca. 15 ml) and thenfiltered, was treated with a solution of 5-bromothiophene-2-sulfonylchloride (0.85g) in DMF (15 ml), followed by N,N-diisopropylethylamine(1.14 ml). The mixture was shaken for 20 h at room temperature,filtered, washed with DMF, DCM and diethyl ether. The resultant solidwas dried in vacuo to give the title compound (1.59 g) as anorange/brown resin. 0.025 g of this resin was treated withtrifluoroacetic acid-DCM (1:1, 1 ml) and shaken for 2 h and filtered.The filtrate was concentrated under a stream of nitrogen to give Example367 (0.0025 g) as an off-white glass.

[1229] Mass spectrum: Found: MH⁺465

Intermediate 100 tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl](2-benzyloxy-2oxoethyl)amino}-2-oxopyrrolidin-1-yl)propanoate

[1230] To a solution of tert-butyl(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino)-2-oxopyrrolidin-1-yl)propanoate(1 g) in DMF (20 ml) was added potassium carbonate (0.92 g) andbenzyl-2-bromoacetate (0.33 g), and the mixture was stirred undernitrogen at room temperature for 72 h. The reaction mixture wasfiltered, concentrated under reduced pressure, and the residuepartitioned between water and DCM. The organic layer was isolated, dried(over magnesium sulphate and purified by SPE (silica, cyclohexane:ethylacetate 2:1) to give the title compound (1.0 g) as a white solid.

[1231] Mass spectrum: Found: MH⁺601

Intermediate 101 BenzylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate

[1232] A mixture of Intermediate 100 (0.5 g) was dissolved in DCM (10ml) and cooled to 0° C., using an ice bath. Trifluoroacetic acid (10 ml)was added dropwise, and the solution left to warm to room temperatureover 2 h. The reaction mixture was concentrated under reduced pressureto give a clear residue (0.45 g) that was dissolved in DCM (20 ml).1-Hydroxybenzotriazole hydrate (0.34 g),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.48 g)and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.39 g) were added, andthe resultant solution was stirred at room temperature for 0.5 h.Triethylamine (0.5 ml) was added, and the resultant mixture stirredunder nitrogen for 72 h. The mixture was washed with water and theaqueous layer re-extracted with DCM. The combined organic layers weredried (over magnesium sulfate), filtered and concentrated under reducedpressure. The residue was purified by mass directed preparative h.p.l.c.to give the title compound (0.18 g) as a white solid.

[1233] Mass spectrum: Found: MH⁺681

Intermediate 102 5-Chloro-1-benzofuran

[1234] To a solution of 5-chloro-1-benzofuran-2-carboxylic acid (0.2 g)in 1-methyl-2-pyrrolidinone (2 ml) was added copper granules (0.2 g).The reaction mixture was heated at 250° C. for 3.5 min in a microwave.The reaction vessel was cooled to room temperature and the mixturecombined with four other similar mixtures and the combined mixturespartitioned between water and diethyl ether. The organic layer waswashed with water and brine, dried (over magnesium sulphate) andconcentrated under reduced pressure to give the title compound (0.65 g)as a yellow oil.

[1235] Gas-chromatography electron-ionisation spectrum: Found: M⁺152, Rt5.72 min

Intermediate 103 5-Chloro-1-benzofuran-2-sulfonyl Chloride

[1236] n-Butyl lithium (1.6M in hexanes, 0.45 ml) was added to a cooled(−78° C.) solution of Intermediate 102 (0.11 g) in anhydrous THF (5 ml)over 5 min. The reaction was stirred for a further 5 min, warmed to 45°C. and stirred for 40 min. The mixture was cooled to −70° C. and sulphurdioxide gas bubbled into the vessel over 7 min. The solution was allowedto warm to room temperature over 45 min, and then concentrated underreduced pressure to give a yellow gum. To a suspension of the gum inanhydrous DCM (4 ml) was added N-chlorosuccinimide (0.118 g) and themixture stirred at room temperature for 75 min. The solution wasfiltered, and the filtrate concentrated under reduced pressure to givethe title compound (0.093 g) as a yellow solid.

[1237] Mass Spectrum: Found: MH⁺260 for dimethylamine quenched sample

Intermediate 104 2-Chloro-4-ethenylphenol

[1238] To a slurry of methyltriphenylphosphonium bromide (0.23 g) in dryTHF (5 ml) under nitrogen at −78° C., n-butyl lithium (1.6M in hexanes,0.37 ml) was added dropwise over 2 min. The mixture was allowed to warmto 0° C., stirred for 20 min, cooled to −78° C. and a solution of3-chloro-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzaldehyde* (0.134g) in dry THF (5 ml) added. The reaction mixture was allowed to reachroom temperature overnight and quenched with saturated aqueous ammoniumchloride. The resultant mixture was extracted with diethyl ether and thecombined organic extracts were concentrated under reduced pressure. Theresidue was purified using SPE (silica, eluting with cyclohexane,followed by 5% to 25% ethyl acetate:cyclohexane) to give the titlecompound (0.049 g) as an oil.

[1239] H.p.l.c. (1) Rt 3.26 min *Boukouvalas, J; Maltais, F; Lachance,N., Tetrahedron Lett. (1994), 35(43), 7897-900.

Intermediate 105 tert-Butyl(2-chloro-4-vinylphenoxy)diphenylsilane

[1240] A mixture of Intermediate 104 (0.038 g), imidazole (0.042 g) andtert-butyldiphenylsilyl chloride (0.083 ml) was stirred in dry DMF (0.5ml) at room temperature under nitrogen for 20 h. The mixture wasquenched with water, extracted with diethyl ether, dried (over magnesiumsulphate), filtered and concentrated under reduced pressure. Theresultant oil was purified using SPE (silica, eluting with cyclohexanefollowed by 5% to 20% ethyl acetate:cyclohexane) to give the titlecompound (0.102 g) as an oil.

[1241] H.p.l.c. (1) Rt4.71 min

Intermediate 106 3tert-Butyl(dimethyl)silyl]oxy}-4-chlorobenzaldehyde

[1242] A mixture of 4-chloro-3-hydroxy-benzaldehyde* (0.354 g),4-N,N-dimethylaminopyridine (0.028 g), tert-butyldimethylsilyl chloride(0.409 g) and triethylamine (0.473 ml) in DCM (15 ml) was stirred atroom temperature under nitrogen for 19 h. The mixture was quenched withsaturated aqueous sodium bicarbonate and extracted with diethyl ether.The combined organic extracts were concentrated under reduced pressureto give an oil which was purified using SPE (silica, eluting withcyclohexane followed by 10% to 30% ethyl acetate-cyclohexane) to givethe title compound (0.42 g) as an oil.

[1243] H.p.l.c. (1) Rt 4.11 min

Intermediate 107 2-Chloro-5-vinylphenol

[1244] The title compound was prepared using Intermediate 106, and thesynthetic procedure described for Intermediate 104.

[1245] H.p.l.c. (1) Rt 3.22 min

Intermediate 108 tert-Butyl(2chloro-5-vinylphenoxy)diphenylsilane

[1246] The title compound was prepared using Intermediate 107, and thesynthetic procedure described for Intermediate 105.

[1247] H.p.l.c. (1) Rt 4.68 min

Intermediate 109(E)-2-(3-{[tert-Butyl(diphenyl)silyl]oxy}-4-chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1248] Sulphuryl chloride (0.103 ml) was added dropwise to DMF (0.116ml) at 0° C. under nitrogen, over 5 min. The mixture was allowed toreach room temperature and stirred for 30 min. Intermediate 108 (0.293g) in cyclohexane (0.2 ml) was added in one portion and the resultantmixture was heated at 90° C. for 6 h. The cooled mixture was poured ontocrushed ice, extracted with diethyl ether, dried (over sodium sulphate)and concentrated under reduced pressure. This crude sulfonyl chloridewas treated with Intermediate 87 (0.134 g), 4-dimethylaminopyridine(0.0068 g), di-isopropylethylamine (0.192 ml) in dry DCM (5 ml), andafter stirring for 3 days at room temperature under nitrogen, themixture was concentrated under reduced pressure. The resultant solutionwas washed with water and filtered through a hydrophobic frit. Thefiltrate was concentrated under reduced pressure, and the remaining oilpurified by SPE (silica, eluting with cyclohexane/ethyl acetate 19:1 andthen 10:1) followed by mass directed preparative h.p.l.c. to give thetitle compound (0.0078 g) as a colourless gum.

[1249] Mass spectrum: Found: MH⁺696

Intermediate 110 Ethyl2-azido-4-{[1-(tert-butoxycarbonyl)propyl]amino}butanoate

[1250] To a solution of tert-butyl 2-amino-butanoate (0.397 g) and ethyl2-azido-4-bromo-butanoate (0.286 g) in acetonitrile (5 ml) was addedtriethylamine (0.347 ml). The mixture was heated at 50° C. for 18 h,cooled and evaporated onto silica gel (Merck.7734). The pre-absorbedmaterial was purified by flash column chromatography (Merck. 9385,eluting with cyclohexane:ethyl acetate 6:1) to give the title compound(0.200 g) as a mixture of four diastereomers.

[1251] Mass spectrum: Found: MH⁺315

Intermediate 1112-Azido-4-{[1-(tert-butoxycarbonyl)propyl]amino}butanoic acid

[1252] To a solution of Intermediate 110 (0.2 g) in THF (3 ml) and water(3 ml) was added lithium hydroxide (0.038 g) and the resultant solutionwas stirred at room temperature for 18 h. The pH of the reaction mixturewas adjusted to pH5 with 2N aqueous HCl. The mixture was thenconcentrated under reduced pressure to give the title compound (0.187 g)as a mixture of four diastereomers.

[1253] Mass spectrum: Found: MH⁺ 287

Intermediate 112 and Intermediate 113 tert-Butyl2-(3-azido-2-oxopyrrolidin-1-yl)butanoate [Mixture 1 and Mixture 2]

[1254] A solution of Intermediate 111 (0.187 g), diphenylphosphorylazide (0.281 ml) and triethylamine (0.364 ml) in DMF (5 ml) was stirredat room temperature for 48 h and then concentrated under reducedpressure. The mixture was partitioned between ethyl acetate and waterand the organic extract was concentrated under reduced pressure. Theresultant oil was purified by flash chromatography (Merck. 9385, elutingwith cyclohexane:ethyl acetate 1:1) to give the title diastereomericcompounds as two enantiomeric pairs (0.051 g and 0.039 g).

[1255] Mass Spectrum: Found: MH⁺ 269 for both Mixture 1 and Mixture 2

Intermediate 114 tert-Butyl2-(3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)butanoate[Isomer 1 and Isomer 2]

[1256] A mixture of Intermediate 112 [Mixture 1] (0.051 g), 10%palladium on carbon (0.01 g) and ethanol (5 ml) was stirred under anatmosphere of hydrogen for 18 h. The reaction mixture was filteredthrough Celite™ and the filtrate was concentrated under reduced pressureto give a yellow gum. The gum (0.034 g) in DCM (2 ml) was treated with6-chloronaphthylsulphonyl chloride¹ (0.04 g) and N,N-diisopropylamine(0.073 ml) and stirred at room temperature for 24 h. The mixture waswashed with water and concentrated under reduced pressure to yield anoil which was partially purified using SPE (silica, eluting withcyclohexane:ethyl acetate 1:1) to give the title compound (0.043 g) as awhite solid.

[1257] Mass spectrum: Found: MH⁺ 467

[1258] Using Intermediate 113 and similar chemistry to that describedabove, the following was prepared:

Intermediate 115 tert-Butyl2-(3-{[(6-chloro-2-naphthyl)sulfonyl}amino)-2-oxopyrrolidin-1-yl)butanoate[Isomer 3 and Isomer 4]

[1259] Mass spectrum: Found: MH⁺ 467

Intermediate 1162-(3-{[(6-Chloro-2-naphthyl)sulfonyl[amino}-2-oxopyrrolidin-1-yl)butanoicacid [Isomer 1 and Isomer 2

[1260] Using Intermediate 114 and the synthetic procedure described forIntermediate 13, the title compound was prepared.

[1261] H.p.l.c. (1) Rt 3.11 min

Intermediate 1172-(3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)butanoicacid [Isomer 3 and Isomer 4]

[1262] Using Intermediate 115 and the synthetic procedure described forIntermediate 13, the title compound was prepared.

[1263] H.p.l.c. (1) Rt 3.20 min

Intermediate 118 5-Chlorothieno[3,2-b]pyridine-2-sulfonyl chloride

[1264] 5-Chlorothieno[3,2-b]pyridine* (0.2 g) was dissolved in anhydrousTHF (10 ml) under nitrogen and cooled to −70° C. n-Butyllithium (1.6M inhexanes, 0.780 ml) was added dropwise over 10 min and the mixturestirred for a further 5 min. The mixture was warmed to −50° C. andstirred for 55 min. The reaction was cooled to −70° C., and sulphurdioxide gas was bubbled through the reaction for 10 min. The reactionwas allowed to warm to room temperature and concentrated under reducedpressure to give a yellow residue which was re-suspended in anhydrousDCM (6 ml) and treated with N-chlorosuccinimide (0.189 g). The mixturewas stirred for 2 h at room temperature and any remaining solid removedby filtration. The filtrate was concentrated under reduced pressure togive the title compound (0.153 g) as a white solid.

[1265] Mass Spectrum: Found: MH⁺ 277 for dimethylamine quenched massspectrum sample *Barker. J. N, et.al., J. Chem. Res. (1984), (3),771-795.

Intermediate 119(2R)-2-(3-{[(6-Bromo-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid

[1266] Using Intermediate 33 and 6-bromo-2-naphthalenesulfonyl chlorideand similar chemistry to that described for Intermediates 35 and 37, thetitle compound was prepared.

[1267] Mass spectrum: Found: MH⁺ 442

Intermediate 120(2R)-2-(3-{[(5-Chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid

[1268] Using Intermediate 33 and5-chloro-3-methylbenzo[b]thiophene-2-sulphonyl chloride and similarchemistry to that described for Intermediates 35 and 37, the titlecompound was prepared.

[1269] Mass spectrum: Found: MH⁺ 417

Example 16-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1270] To a solution of(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid [Intermediate 29] (0.105 g) in DCM (10 ml) were added1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (0.152 g),HOBT (0.107 g) and triethylamine (0.222 ml) and the mixture was stirredat room temperature for 30 min. Morpholine (0.07 ml) was added and theresultant mixture stirred at room temperature for 16 h. The mixture waspartitioned between DCM and water. The aqueous layer was re-extractedwith DCM and the combined, dried (over magnesium sulphate) organicextracts were concentrated under reduced pressure. The residue waspurified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1,and ethyl acetate) to give the title compound (0.1 g) as a white solid.

[1271] Mass spectrum: Found: MH⁺ 466 H.p.l.c. (1) Rt 3.13 min ¹H NMR(D₄MeOH): δ 3 8.54(1H, br.s), 8.08-7.96(4H, m), 7.63(1H, dd), 5.00(1 H,q), 4.18(1H, dd), 3.69-3.46(9H, m), 3.31-3.29(1H, m), 2.27(1H, m),1.77(1H, m), 1.26(3H, d) ppm.

[1272] The title compound could also be prepared using Intermediate 87and 6-chloronaphthalene sulphonyl chloride¹, and the chemistry describedfor the preparation of Example 386 (Route 1).

[1273] Using similar chemistry to that described for Example 1, thefollowing were prepared:

Example 26-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1274] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.22 min

Example 36-Chloro-N-{(3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1275] The title compound was isolated from a crude reaction mixtureusing mass directed preparative h.p.l.c.

[1276] Mass spectrum: Found: MH⁺ 533 H.p.l.c. (1) Rt 2.64 min

Example 46-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1277] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.1 min

Example 56-Chloro-N-[(3S)-1-{(1S)-2-{-2-[(diethylamino)methyl]piperidin-1-yl]-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1278] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.5 min

Example 66-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1279] Mass spectrum: Found: MH⁺ 547 H.p.l.c. (1) Rt 2.76 min

Example 71-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidine-3-carboxamide

[1280] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 3.06 min

Example 86-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-{[(trifluoromethyl)sulfonyl]amino)piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1281] Mass spectrum: Found: MH⁺ 612 H.p.l.c. (1) Rt 3.59 min

Example 91-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidine-2-carboxamide

[1282] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 3.16 min

Example 101-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-4-carboxamide

[1283] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 3.04 min

Example 116-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperazin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamidetrifluoroacetate

[1284] tert-Butyl4-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperazine-1-carboxylatewas prepared using the generic method as described for Example 1. Thetitle compound was prepared using the synthetic procedure as describedfor Intermediate 13.

[1285] Mass spectrum: Found: MH⁺ 465 H.p.l.c. (1) Rt 2.48 min

Example 126-Chloro-N-{(3S)-1-[(1S)-1-methyl-2oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1286] Mass spectrum: Found: MH⁺ 493 H.p.l.c. (1) Rt 2.74 min

Example 136-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1287] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 2.81 min

Example 146-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{2-[(4-methylpiperazin-1-yl)methyl]pyrrolidin-1-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate

[1288] Mass spectrum: Found: MH⁺ 562 H.p.l.c. (1) Rt 2.53 min

Example 156-Chloro-N-((3S)-1-(1S)-1-methyl-2-[2-(morpholin-4-ylmethyl)pyrrolidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1289] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.56 min

Example 166-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1290] Mass spectrum: Found: MH⁺ 450 H.p.l.c. (1) Rt 3.0 min

Example 176-Chloro-N-{(3S)-1-[(1S)-2-(2,6-dimethylmorpholin-4-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1291] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.16 min

Example 186-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1292] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 2.93 min

Example 196-Chloro-N-{(3S)-1-(1S)-1-methyl-2-(3-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1293] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 3.23 min

Example 206-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide[Isomer 1]

[1294] Mass spectrum: Found: MH⁺ 561 H.p.l.c. (1) Rt 2.73 min

Example 216-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl)-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide[Isomer 2

[1295] Mass spectrum: Found: MH⁺ 561 H.p.l.c. (1) Rt 2.74 min

Example 22

[1296] Methyl1-(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-2-carboxylate

[1297] Mass spectrum: Found: MH⁺ 522 H.p.l.c. (1) Rt 3.57 min

Example 236-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(pyrrolidin-1-ylcarbonyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1298] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 3.08 min

Example 246-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{2-[(methylsulfonyl)methyl]morpholin-4-yl-}2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1299] Mass spectrum: Found: MH⁺ 558 H.p.l.c. (1) Rt 3.17 min

Example 256-Chloro-N-((3S)-1-(1S)-2-[2-(methoxymethyl)morpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1300] Mass spectrum: Found: MH⁺ 510 H.p.l.c. (1) Rt 3.02 min

Example 26 and Example 274-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-methylmorpholine-2-carboxamide[Isomer 1 and Isomer 2]

[1301] Isomer 1 Mass spectrum: Found: MH⁺ 523 H.p.l.c. (1) Rt 2.93 minIsomer 2 Mass spectrum: Found: MH⁺ 523 H.p.l.c. (1) Rt 2.96 min

Example 286-Chloro-N-((3S)-1-(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylcarbonyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1302] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 3.04 min

Example 294-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino-}2-oxopyrrolidin-1-yl)propanoyl]-N,N-dimethylmorpholine-2-carboxamide

[1303] Mass spectrum: Found: MH⁺ 537 H.p.l.c. (1) Rt 2.96 min

Example 30 Example 31 and Example 324-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]-N-(2-hydroxypropyl)morpholine-2-carboxamide[Isomer 1, Isomer 2 and Isomer 3Isomer 1]

[1304] Mass spectrum: Found: MH⁺ 567 H.p.l.c. (1) Rt 2.92 min Isomer 2Mass spectrum: Found: MH⁺ 567 H.p.l.c. (1) Rt 2.91 min Isomer 3 Massspectrum: Found: MH⁺ 567 H.p.l.c. (1) Rt 2.92 min

Example 334-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N,N-diisopropylmorpholine-2-carboxamide

[1305] Mass spectrum: Found: MH⁺ 593 H.p.l.c. (1) Rt 3.4 min

Example 346-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(piperidin-1-ylcarbonyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1306] Mass spectrum: Found: MH⁺ 577 H.p.l.c. (1) Rt 3.21 min

Example 356-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{2-[(methylamino)methyl]morpholin-4-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate

[1307] Mass spectrum: Found: MH⁺ 509 H.p.l.c. (1) Rt 2.58 min

Example 366-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)morpholin-4-ylethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1308] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.58 min

Example 376-Chloro-N-{(3S)-1-[(1S)-2-(2-{[(2-hydroxypropyl)amino]methyl}morpholin-4-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate

[1309] Mass spectrum: Found: MH⁺ 553 H.p.l.c. (1) Rt 2.55 min

Example 38 and Example 396-Chloro-N-{(3S)-1-((1S)-2-{2-[(dimethylamino)methyl]morpholin-4-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate (Isomer 1 and Isomer 2]

[1310] Isomer 1 Mass spectrum: Found: MH⁺ 523 H.p.l.c. (1) Rt 2.54 minIsomer 2 Mass spectrum: Found: MH⁺ 523 H.p.l.c. (1) Rt 2.55 min

Example 406-Chloro-N-[(3S)-1-((1S)-2-{2-[(diisopropylamino)methyl]morpholin-4-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate

[1311] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 2.67 min

Example 416-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(piperidin-1-ylmethyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1312] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 2.62 min

Example 42 and Example 436-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide[Isomer 1 and Isomer 2]

[1313] Isomer 1 Mass spectrum: Found: MH⁺ 528 H.p.l.c. (1) Rt 2.78 minIsomer 2 Mass spectrum: Found: MH⁺ 528 H.p.l.c. (1) Rt 2.81 min

Example 446-Chloro-N-{(3S)-1-[(1S)-2-(3,3-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1314] Mass spectrum: Found: MH⁺ 500 H.p.l.c. (1) Rt 3.34 min

Example 456-Chloro-N-{(3S)-1-[(1S)-2-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1315] Mass spectrum: Found: MH⁺ 500 H.p.l.c. (1) Rt 3.33 min

Example 46N-{(3S)-1-[(1S)-2-Azetidin-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1316] Mass spectrum: Found: MH⁺ 436 H.p.l.c. (1) Rt2.99 min

Example 476-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxyazetidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1317] Mass spectrum: Found: MH⁺ 452 H.p.l.c. (1) Rt 2.99 min

Example 486-Chloro-N-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1318] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.15 min

Example 496-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydro-1,6-naphthyridin-1(2H)-yl)-1-methyl-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1319] Mass spectrum: Found: MH⁺ 513 H.p.l.c. (1) Rt 2.66 min

Example 50 6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1320] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 2.93 min

Example 51N-((3S)-1-{(1S)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide

[1321] Mass spectrum: Found: MH⁺ 476 H.p.l.c. (1) Rt 3.17 min

Example 526-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate

[1322] Mass spectrum: Found: MH⁺ 527 H.p.l.c. (1) Rt 2.67 min

Example 536-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate

[1323] Mass spectrum: Found: MH⁺ 527 H.p.l.c. (1) Rt 2.66 min

Example 546-Chloro-N-{1-[(1S)-1-methyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl-1-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1324] Using Intermediate 38, and the synthetic procedure described forExample 1, the title compound was prepared.

[1325] Mass spectrum: Found: MH⁺ 479 H.p.l.c. (1) Rt 2.93 min

[1326] Using similar chemistry, the following was prepared:

Example 55 N-{1[(1S)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1327] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 2.93 min

Example 56N-{(3S)-1-[(1S)-2-(2-Azabicyclo[2.2.2]oct-2-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1328] Mass spectrum: Found: MH⁺ 490 H.p.l.c. (1) Rt 3.28 min

Example 576-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1329] Using Intermediate 31, and the synthetic procedure described forExample 1, the title compound was prepared.

[1330] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.28 min

[1331] Using similar chemistry, the following were prepared:

Example 586-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1332] Mass spectrum: Found: MH⁺ 466 H.p.l.c. (1) Rt 2.96 min

Example 596-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1333] Mass spectrum: Found: MH⁺ 450 H.p.l.c. (1) Rt 3.12 min

Example 606-Chloro-N-((3R)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1334] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.38 min

Example 616-Chloro-N-[(3R)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1335] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.67 min

Example 625′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1336] tert-Butyl(2S)-2-((3S)-3-{[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.217 g) was dissolved in DCM (2 ml) and treated with trifluoroaceticacid (2 ml) and stirred at room temperature for 2 h. The mixture wasthen concentrated under reduced pressure to give an oil which wassubsequently dissolved in DCM (5 ml) and treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.256 g),HOBT (0.184 g) and triethylamine (0.375 ml). After the solution had beenstirred at room temperature for 30 min, morpholine (0.117 ml) was addedand the resultant mixture stirred for a further 20 h. The mixture wasconcentrated under reduced pressure and the residue partitioned betweenDCM and water. The organic component was washed with water and brine,and concentrated under reduced pressure. The residue was purified usingSPE (silica, eluting with cyclohexane; cyclohexane:ethyl acetate 4:1,1:1, 1:4; ethyl acetate; methanol:ethyl acetate 1:10; methanol) to givethe title compound (0.078 g) as a white solid.

[1337] Mass spectrum: Found: MH⁺ 504 H.p.l.c. (1) Rt 3.17 min ¹H NMR(D₄MeOH): δ 7.61(1H, d), 7.23(1H, d), 7.22(1H, d), 7.03(1H, d), 5.04(1H,q), 4.21(1H, dd), 3.69-3.46(9H, m), 3.39-3.35(1H, m), 2.39(1H, m),1.86(1H, m), 1.30(3H, d) ppm.

Example 635′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide

[1338] Using Intermediate 71 and the synthetic procedure described forExample 62, the title compound was prepared.

[1339] Mass spectrum: Found: MH⁺ 641 H.p.l.c. (1) Rt 2.98 min

Example 64(E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)ethenesulfonamideformate

[1340] Using Intermediate 72 and the synthetic procedure described forExample 62, the title compound was prepared.

[1341] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 2.75 min

Example 656-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide

[1342] Using Intermediate 73 and the synthetic procedure described forExample 62, the title compound was prepared.

[1343] Mass spectrum: Found: MH⁺ 609 H.p.l.c. (1) Rt 2.77 min

Example 665-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide

[1344] Using Intermediate 74 and the synthetic procedure described forExample 62, the title compound was prepared.

[1345] Mass spectrum: Found: MH⁺ 609 H.p.l.c. (1) Rt 2.77 min

Example 675′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide

[1346] tert-Butyl(2S)-2-((3S)-3-{[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.217 g) was dissolved in DCM (2 ml) and treated with trifluoroaceticacid (2 ml) and stirred at room temperature for 2 h. The mixture wasthen concentrated under reduced pressure to give an oil which wassubsequently dissolved in DCM (5 ml) and treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.256 g),HOBT (0.184 g) and triethylamine (0.375 ml). After the solution had beenstirred at room temperature for 30 min,(S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.219 ml) was added and theresultant mixture stirred for a further 20 h. The mixture wasconcentrated under reduced pressure and the residue partitioned betweenDCM and water. The organic component was washed with water and brine,and concentrated under reduced pressure. The residue was purified usingSPE (silica, eluting with cyclohexane; cyclohexane:ethyl acetate 4:1,1:1, 1:4; ethyl acetate; methanol:ethyl acetate 1:10; methanol) to givethe title compound (0.042 g) as a white solid.

[1347] Mass spectrum: Found: MH⁺ 571 H.p.l.c. (1) Rt 2.77 min

Example 68(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1348] Using Intermediate 68 and the synthetic procedure described forExample 62, the title compound was prepared.

[1349] Mass spectrum: Found: MH⁺ 442 H.p.l.c. (1) Rt 2.86 min ¹H NMR(CDCl₃):δ 7.46(1H, d), 7.44(2H, d), 7.38(2H, d), 6.89(1H, d), 5.35(1H,br.d), 5.05(1H, q), 4.00(1H, m), 3.69-3.48(9H, m), 3.35(1H, m), 2.62(1H,m), 2.06(1H, m), 1.33(3H, d) ppm.

Example 69N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1350] Using Intermediate 75 and the synthetic procedure described forExample 62, the title compound was prepared.

[1351] Mass spectrum: Found: MH⁺ 499 H.p.l.c. (1) Rt 2.81 min

Example 70(E)-2-(4-Chlorophenyl)-N-((3S)-1-(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)ethenesulfonamide

[1352] Using Intermediate 68 and the synthetic procedure described forExample 67, the title compound was prepared.

[1353] Mass spectrum: Found: MH⁺ 509 H.p.l.c. (1) Rt 2.5 min

Example 71N2-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1354] Using Intermediate 76 and the synthetic procedure described forExample 62, the title compound was prepared.

[1355] Mass spectrum: Found: MH⁺ 561 H.p.l.c. (1) Rt 2.96 min

Example 725′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1356] Using Example 62 and the synthetic procedure described forExample 293, the title compound was prepared.

[1357] Mass spectrum: Found: MH⁺ 543 H.p.l.c. (1) Rt 3.34 min

[1358] Using similar chemistry, the following were prepared:

Example 73 MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate

[1359] Mass spectrum: Found: MH⁺ 576 H.p.l.c. (1) Rt 3.34 min

Example 745′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide

[1360] Mass spectrum: Found: MH⁺ 574 H.p.l.c. (1) Rt 3.4 min

Example 75N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine

[1361] Using standard alkaline hydrolysis conditions, the title compoundwas prepared from Example 73.

[1362] Mass spectrum: Found: MH⁺ 562 H.p.l.c. (1) Rt 3.21 min

Example 76(E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-1-(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1363] Using Example 68 and bromoacetonitrile, and the syntheticprocedure described for Example 293, the title compound was prepared.

[1364] Mass spectrum: Found: MH⁺ 481 H.p.l.c. (1) Rt 3.05 min

[1365] Using similar chemistry, the following were prepared:

Example 77(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide

[1366] Mass spectrum: Found: MH⁺ 512 H.p.l.c. (1) Rt 3.11 min

Example 78 MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate

[1367] Mass spectrum: Found: MH⁺ 514 H.p.l.c. (1) Rt 3.05 min

Example 79N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine

[1368] Using standard alkaline hydrolysis conditions, the title compoundwas prepared from Example 78.

[1369] Mass spectrum: Found: MH⁺ 500 H.p.l.c. (1) Rt 2.9 min

Example 80(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1370] tert-Butyl(2S)-2-[(3S)-3-({[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}amino)-2-oxopyrrolidin-1-yl]propanoate(0.192 g) was dissolved in DCM (2 ml) and treated with trifluoroaceticacid (2 ml) and stirred at room temperature for 2 h. The mixture wasthen concentrated under reduced pressure to give an oil which wassubsequently dissolved in DCM (5 ml) and treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.256 g),HOBT (0.184 g) and triethylamine (0.375 ml). After the solution had beenstirred at room temperature for 30 min, piperidine (0.133 ml) was addedand the resultant mixture stirred for a further 20 h. The mixture wasconcentrated under reduced pressure and the residue partitioned betweenDCM and water. The organic component was washed with water and brine,and concentrated under reduced pressure. The residue was purified usingSPE (silica, eluting with cyclohexane; cyclohexane:ethyl acetate 4:1,1:1, 1:4; ethyl acetate; methanol:ethyl acetate 1:10; methanol) to givethe title compound (0.042 g) as a white solid.

[1371] Mass spectrum: Found: MH⁺ 440 H.p.l.c. (1) Rt 3.1 min

Example 81 MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-pieridin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate

[1372] Using Example 80 and methyl bromoacetate, and the syntheticprocedure described for Example 293, the title compound was prepared.

[1373] Mass spectrum: Found: MH⁺ 512 H.p.l.c. (1) Rt 3.3 min

[1374] Using similar chemistry, the following was prepared:

Example 82(E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl-1-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1375] Mass spectrum: Found: MH⁺ 479 H.p.l.c. (1) Rt 3.31 min

Example 83N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-1-2-oxopyrrolidin-3-yl}glycine

[1376] Using standard alkaline hydrolysis conditions, the title compoundwas prepared from Example 81.

[1377] Mass spectrum: Found: MH⁺ 498 H.p.l.c. (1) Rt 3.16 min

Example 84N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1378] tert-Butyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate(0.6 g) was dissolved in DCM (11 ml) and trifluoroacetic acid (11 ml)was added. The mixture was stirred at room temperature for 2 h and thenconcentrated under reduced pressure. The residue was dissolved in water(5 ml) and ammonia solution (0.88%; 1 ml) added. The resultant aqueousmixture was extracted with DCM. The combined organic extracts were dried(over magnesium sulphate), filtered and concentrated under reducedpressure to give the title compound (0.38 g) as a white foam.

[1379] Mass spectrum: Found: MH⁺ 479 H.p.l.c. (1) Rt 2.71 min

Example 856-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1380] To polymer N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene (0.038 g) in an Alltech™ tube was added a solution of(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (0.007 g) in DCM (0.9 ml) followed by 3-methylpiperidine (0.0025 g)in DMF (0.1 ml) and N,N-diisopropylethylamine (0.006 ml). The mixturewas shaken at room temperature for 4 days. The tube was drained, thefiltrate collected and the resin washed with DCM. The combined DCMsolutions were concentrated under reduced pressure and the residuepurified by mass directed preparative h.p.l.c. to give the titlecompound (0.0023 g) as a white solid.

[1381] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.25 min

[1382] Using similar chemistry, the following were prepared:

Example 866-Chloro-N-((3S)-1-{(1S)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1383] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 2.93 min

Example 87N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide

[1384] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 2.86 and 2.97 min(two diastereoisomers)

Example 886-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(1H-pyrrol-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1385] Mass spectrum: Found: MH⁺ 543 H.p.l.c. (1) Rt 3.57 min

Example 896-Chloro-N-{(3S)-1-[(1S)-2-(3,3-dimethylpiperidine-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1386] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.51 min

Example 906-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1387] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.21 min

Example 916-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(trifluoromethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1388] Mass spectrum: Found: MH⁺ 532 H.p.l.c. (1) Rt 3.52 min

Example 926-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1389] The title compound was isolated from a crude reaction mixtureusing mass directed preparative h.p.l.c.

[1390] Mass spectrum: Found: MH⁺ 561 H.p.l.c. (1) Rt 2.8 min

Example 936-Chloro-N-{(3S)-1-[(1S)-2-(3-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1391] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.04 min

Example 946-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1392] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.43 min

Example 956-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1393] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 3.05 min

Example 966-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-octahydroquinolin-1(2H)-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1394] Mass spectrum: Found: MH⁺ 518 H.p.l.c. (1) Rt 3.55 min

Example 976-Chloro-N-{(3S)-1-[(1S)-2-(4-hydroxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1395] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 3.00 min

Example 986-Chloro-N-{(3S)-1-[(1S)-2-[2-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1396] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.16 min

Example 991-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl}-N,N-diethylpiperidine-3-carboxamide

[1397] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 3.27 min

Example 1006-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-phenylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1398] Mass spectrum: Found: MH⁺ 530 H.p.l.c. (1) Rt 3.68 min

Example 1016-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-phenylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1399] Mass spectrum: Found: MH⁺ 540 H.p.l.c. (1) Rt 3.66 min

Example 1026-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1400] Mass spectrum: Found: MH⁺ 561 H.p.l.c. (1) Rt 3.32 min

Example 1036-Chloro-N-((3S)-1-{(1S)-2-[4-(dimethylamino)piperidin-1-yl[-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1401] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 2.64 min

Example 1041-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N,N-dimethylprolinamide

[1402] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 3.05 min

Example 105N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]pyrrolidin-3-yl}acetamide

[1403] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 2.96 min

Example 1066-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxypyrrolidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1404] Mass spectrum: Found: MH⁺ 466 H.p.l.c. (1) Rt 2.95 min

Example 107 Methyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-L-prolinate

[1405] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.2 min

Example 1086-Chloro-N-{(3S)-1-[(1S)-2-(4-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1406] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.17 min

Example 1096-Chloro-N-((3S)-1-{(1S)-2-[4-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1407] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.06 min

Example 110 Methyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2oxopyrrolidin-1-yl)pronanoyl]piperidine-4-carboxylate

[1408] Mass spectrum: Found: MH⁺ 522 H.p.l.c. (1) Rt 3.32 min

Example 111 Methyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2oxopyrrolidin-1-yl)pronanoyl]piperidine-3-carboxylate

[1409] Mass spectrum: Found: MH⁺ 522 H.p.l.c. (1) Rt 3.32 min

Example 1122-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]pyrrolidin-2-yl}acetamide

[1410] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 2.98 min

Example 113N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-4-yl}acetamide

[1411] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 2.98 min

Example 1146-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-oxopiperazin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1412] Mass spectrum: Found: MH⁺ 479 H.p.l.c. (1) Rt 2.94 min

Example 1156-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{3-[(methylamino)methyl]pyrrolidin-1-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamideformate

[1413] Mass spectrum: Found: MH⁺ 493 H.p.l.c. (1) Rt 2.65 min

Example 1166-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(4-phenylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1414] Mass spectrum: Found: M⁺ 540 H.p.l.c. (1) Rt 3.64 min

Example 117N-{(3S)-1-[(1S)-2-(4-Acetylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1415] Mass spectrum: Found: MH⁺ 506 H.p.l.c. (1) Rt 3.16 min

Example 118N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]pyrrolidin-3-yl}benzamide

[1416] Mass spectrum: Found: MH⁺ 569 H.p.l.c. (1) Rt 3.28 min

Example 1196-Chloro-N-((3S)-1-{(1S)-2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1417] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.24 min

Example 120 Ethyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidine-2-carboxylate

[1418] Mass spectrum: Found: MH⁺ 536 H.p.l.c. (1) Rt 3.49 min

Example 1216-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylpyrrolidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1419] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.27 min

Example 1226-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(4-pyrrolidin-1-ylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1420] Mass spectrum: Found: MH⁺ 533 H.p.l.c. (1) Rt 2.65 min

Example 1231-[(2S)-2-((3S)-3-{[(6-Chloro-2-napnhthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]prolinamide

[1421] Mass spectrum: Found: MH⁺ 493 H.p.l.c. (1) Rt 2.95 min

Example 1246-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[2-(4-methylpyridin-2-yl)pyrrolidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1422] Mass spectrum: Found: MH⁺ 541 H.p.l.c. (1) Rt 3.0 min

Example 1256-Chloro-N-{(3S)-1-[(1S)-2-(3-isopropyltetrahydropyrimidin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1423] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 2.69 min

Example 1266-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2S)-2-(morpholin-4-ylmethyl)pyrrolidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1424] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.68 min

Example 1276-Chloro-N-{(3S)-1-[(1S)-1-methyl-2oxo-2-(4,6,7,8-tetrahydro-5H-thieno[3,2-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1425] Mass spectrum: Found: MH⁺ 532 H.p.l.c. (1) Rt 3.54 min

Example 1286-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1426] Mass spectrum: Found: MH⁺ 502 H.p.l.c. (1) Rt 2.67 min

Example 1296-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3,5,6,7-tetrahydro-4H-[1,2,3]triazolo[4,5-b]pyridin-4-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1427] Mass spectrum: Found: MH⁺ 503 H.p.l.c. (1) Rt 3.33 min

Example 1306-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydroquinolin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1428] Mass spectrum: Found: MH⁺ 512 H.p.l.c. (1) Rt 3.59 min

Example 1316-Chloro-N-{(3S)-1-[(1S)-2-(3,4-dihydroisoquinolin-2(1H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1429] Mass spectrum: Found: MH⁺ 512 H.p.l.c. (1) Rt 3.52 min

Example 1326-Chloro-N-{(3S)-1-[(1S)-2-(2,3-dihydro-1H-indol-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1430] Mass spectrum: Found: MH⁺ 498 H.p.l.c. (1) Rt 3.58 min

Example 1336-Chloro-N-{(3S)-1-[(1S)-2-(1,3-dihydro-2H-isoindol-2-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1431] Mass spectrum: Found: MH⁺ 498 H.p.l.c. (1) Rt 3.44 min

Example 1346-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1432] Mass spectrum: Found: MH⁺ 526 H.p.l.c. (1) Rt 3.57 min

Example 1351-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-L-proline

[1433] The title compound was prepared by alkaline hydroysis (lithiumhydroxide) of the corresponding methyl ester, Example 107.

[1434] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.03 min

Example 1361-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-3-carboxylicacid

[1435] The title compound was prepared by alkaline hydrolysis (lithiumhydroxide) of the corresponding methyl ester, Example 111.

[1436] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.0 min

Example 1371-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-4-carboxylicacid

[1437] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.01 min

Example 1386-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1438] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 3.01 min

Example 1396-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1439] Mass spectrum: Found: MH⁺ 493 H.p.l.c. (1) Rt 2.95 min

Example 1406-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-thiomorpholin-4-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1440] Mass spectrum: Found: MH⁺ 482 H.p.l.c. (1) Rt 3.34 min

Example 1416-Chloro-N-{(3S)-1-[(1S)-2-(2,5-dihydro-1H-pyrrol-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1441] Mass spectrum: Found: MH⁺ 448 H.p.l.c. (1) Rt 3.08 min

Example 1426-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1442] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 3.17 min

Example 1436-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1443] Mass spectrum: Found: MH⁺ 493 H.p.l.c. (1) Rt 2.64 min

Example 1446-Chloro-N-{(3S)-1-[(1S)-2-(3,6-dihydropyridin-1-(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1444] Mass spectrum: Found: MH⁺ 462 H.p.l.c. (1) Rt 3.3 min

Example 1456-Chloro-N-{(3S)-1-[(1S)-2-(1,1-dioxidothiomorpholin-4-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1445] Mass spectrum: Found: MH⁺ 514 H.p.l.c. (1) Rt 3.12 min

Example 1466-Chloro-N-{(3S)-1-[(1S)-2-(3-hydroxyquinoxalin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1446] Mass spectrum: Found: MH⁺ 527 H.p.l.c. (1) Rt 3.23 min

Example 1475′-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1447] To a solution of(3R)-3-amino-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]pyrrolidin-2-one(0.01 g) in acetonitrile (1 ml) was added triethylamine (0.008 ml) and5′-chloro-2,2′-bithiophene-5-sulfonyl chloride² (0.013 g) and themixture stirred at room temperature for 24 h. The mixture wasconcentrated under reduced pressure and the residue purified by massdirected preparative h.p.l.c. to give the title compound (0.004 g) as awhite solid.

[1448] Mass spectrum: Found: MH⁺ 502 H.p.l.c. (1) Rt 3.43 min

[1449] Using similar chemistry, the following was prepared:

Example 148(E)-2-(4Chlorophenyl)-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-pieridin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1450] Mass spectrum: Found: MH⁺ 440 H.p.l.c. (1) Rt 3.11 min

Example 149 tert-Butyl1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate

[1451] The title compound was prepared using Intermediate 29 andtert-butyl piperidin-3-ylcarbamate, and the synthetic proceduredescribed for Example 1.

[1452] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 3.53 min

Example 150N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide

[1453] To a solution ofN-((3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide(0.005 g) in DMF (0.5 ml) were added propiolic acid (0.001 g),N,N-diisopropylethylamine (0.0044 ml) ando-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.004 g). The mixture was stirred at roomtemperature for 18 h and then concentrated under reduced pressure. Theresidue was partitioned between DCM and saturated sodium bicarbonatesolution and then passed through a hydrophobic frit. The separatedorganic fraction was concentrated under reduced pressure to give thetitle compound (0.0064 g) as an oil.

[1454] Mass spectrum: Found: MH⁺ 531 H.p.l.c. (1) Rt 3.42 min

[1455] Using similar chemistry, the following were prepared:

Example 151N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl)-1-methyl-1H-pyrrole-3-carboxamide

[1456] Mass spectrum: Found: MH⁺ 586 H.p.l.c. (1) Rt 3.32 min

Example 152 Methyl4-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoate

[1457] Mass spectrum: Found: MH⁺ 593 H.p.l.c. (1) Rt 3.31 min

Example 1534-({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]pieridin-3-yl}amino)-4-oxobutanoicacid

[1458] Using standard alkaline hydrolysis conditions, the title compoundwas prepared from Example 152.

[1459] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 3.02 min

Example 154N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl-1H-1,2,4-triazole-3-carboxamide

[1460] Mass spectrum: Found: MH⁺ 574 H.p.l.c. (1) Rt 3.16 min

Example 155N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-Pyrrole-2-carboxamide

[1461] Mass spectrum: Found: MH⁺ 586 H.p.l.c. (1) Rt 3.33 min

Example 156N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}propanamide

[1462] Mass spectrum: Found: MH⁺ 536 H.p.l.c. (1) Rt 3.18 min

Example 157N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-pyrazole-3-carboxamide

[1463] Mass spectrum: Found: MH⁺ 573 H.p.l.c. (1) Rt 3.29 min

Example 158N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-ethylbutanamide

[1464] Mass spectrum: Found: MH⁺ 577 H.p.l.c. (1) Rt 2.71 min

Example 159N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}cyclopentanecarboxamide

[1465] Mass spectrum: Found: MH⁺ 575 H.p.l.c. (1) Rt 3.55 min

Example 160 N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}pentanediamide

[1466] Mass spectrum: Found: MH⁺ 592 H.p.l.c. (1) Rt 3.12 min

Example 161N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}pyrazine-2-carboxamide

[1467] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.48 min

Example 162N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}-1H-pyrazole-4carboxamide

[1468] Mass spectrum: Found: MH⁺ 573 H.p.l.c. (1) Rt 3.2 min

Example 163N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}malonamide

[1469] Mass spectrum: Found: MH⁺ 564 H.p.l.c. (1) Rt 3.11 min

Example 164N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-methylpropanamide

[1470] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 3.27 min

Example 165N-1-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-3-,N-3-dimethyl-beta-alaninamide

[1471] Mass spectrum: Found: MH⁺ 578 H.p.l.c. (1) Rt 3.4 min

Example 166N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}succinamide

[1472] Mass spectrum: Found: MH⁺ 578 H.p.l.c. (1) Rt 3.09 min

Example 167N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide

[1473] Mass spectrum: Found: MH⁺ 531 H.p.l.c. (1) Rt 3.36 min

Example 168N-{1-[(2S)-2-((3S)-3-}[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1H-pyrrole-2-carboxamide

[1474] Mass spectrum: Found: MH⁺ 572 H.p.l.c. (1) Rt 3.5 min

Example 169N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1-methyl-1H-1,2,3-triazole-4-carboxamide

[1475] Mass spectrum: Found: MH⁺ 588 H.p.l.c. (1) Rt 3.4 min

Example 170N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-1,3-thiazole-2-carboxamide

[1476] Mass spectrum: Found: MH⁺ 590 H.p.l.c. (1) Rt 3.3 min

Example 1716-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(3-{[(trifluoromethyl)sulfonyl]amino}piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1477] Using triflic anhydride and Example 84, the title compound wasprepared as described for Example 150.

[1478] Mass spectrum: Found: MH⁺ 611 H.p.l.c. (1) Rt 3.53 min

Example 172N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N2,N2-dimethylglycinamide

[1479] Mass spectrum: Found: MH⁺ 565 H.p.l.c. (1) Rt 2.63 min

Example 173 Methyl3-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate

[1480] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 2.7 min

Example 174N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide

[1481] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.17 min

Example 175 and Example 176N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}pyridine-2-carboxamide[Isomer 1 and Iosmer 2]

[1482] Isomer 1 Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.48 minIsomer 2 Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.6 min

Example 177N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}-4H-1,2,4-triazole-3-carboxamide

[1483] Mass spectrum: Found: MH⁺ 574 H.p.l.c. (1) Rt 3.23 min

Example 178 and Example 179N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-2-ethylbutanamide[Isomer 1 and Isomer 2]

[1484] Isomer 1 Mass spectrum: Found: MH⁺ 578 H.p.l.c. (1) Rt 2.71 minIsomer 2 Mass spectrum: Found: MH⁺ 578 H.p.l.c. (1) Rt 3.58 min

Example 180N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide

[1485] Mass spectrum: Found: MH⁺ 531 H.p.l.c. (1) Rt 3.36 min

Example 181N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide

[1486] To a solution of nicotinic acid (0.006 g) in DCM (0.5 ml) wereadded 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.018 g), HOBT (0.013 g) and triethylamine 0.017 ml) and the mixturewas stirred at room temperature for 1 h. Example 365 (0.015 g) was addedand the resultant mixture stirred at room temperature for 21 h. Themixture was partitioned between DCM and water. The aqueous layer wasre-extracted with DCM and the combined, dried (over magnesium sulphate)organic extracts were concentrated under reduced pressure. The residuewas purified using SPE (silica, eluting with cyclohexane:ethyl acetate5:1, 1:1, 1:5, and DCM:methanol 25:1, 15:1, 5:1) to give the titlecompound (0.01 g) as a white solid.

[1487] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.24 min

[1488] Using similar chemistry, the following were prepared:

Example 182N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}pyridine-2-carboxamide

[1489] Mass spectrum: Found: MH⁺ 584 H.p.l.c: (1) Rt 3.54 min

Example 183N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide

[1490] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.18 min

Example 184 Methyl3-({(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}amino)-3-oxopropanoate

[1491] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 3.11 min

Example 185N-1-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-,N-2-dimethylglycinamide

[1492] Mass spectrum: Found: MH⁺ 564 H.p.l.c. (1) Rt 2.63 min

Example 186 Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate

[1493] Using Example 366 and the synthetic procedure described inExample 181, the title compound was prepared.

[1494] Mass spectrum: Found: MH⁺ 613 H.p.l.c. (1) Rt 3.46 min

[1495] Using similar chemistry, the following were prepared:

Example 187N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}nicotinamide

[1496] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.07 min

Example 188N-{(3R)-1[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide

[1497] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.38 min

Example 189N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide

[1498] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 3.01 min

Example 190 Methyl3-({(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]pieridin-3-yl}amino)-3-oxopropanoate

[1499] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 3.01 min

Example 191N-1-[(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-N-2-dimethylglycinamide

[1500] Mass spectrum: Found: MH³⁰ 564 H.p.l.c. (1) Rt 2.59 min

Example 1925′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1501] A solution of the(3S)-3-amino-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]pyrrolidin-2-one(0.007 g) in DCM (0.5 ml) was treated with5′-chloro-2,2′-bithiophene-5-sulfonyl chloride² (0.009 g) andtriethylamine (0.0054 ml) and stirred at room temperature for 48 h. Themixture was concentrated under reduced pressure and the residue purifiedusing SPE (silica, eluting with methanol) to give the title compound(0.009 g) as an off-white solid.

[1502] Mass spectrum: Found: MH⁺ 502 H.p.l.c. (1) Rt 3.39 min

[1503] Using Intermediates 21, 22, 23 and 24, and chemistry to thatdescribed for the preparation of Example 192, the following wereprepared:

Example 1934′-Fluoro-N-{(3S)-1-[(1S)-1-methyl-2oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1,1′-biphenyl-4-sulfonamide

[1504] Mass spectrum: Found: MH⁺ 472 H.p.l.c. (1) Rt 3.17 min

Example 1946-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1505] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.22 min

Example 195(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1506] Mass spectrum: Found: MH⁺ 439 H.p.l.c. (2) Rt 5.93 min

Example 1966-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide(1:1)

[1507] Mass spectrum: Found: MH⁺ 469 H.p.l.c. (2) Rt 6.83 min

Example 1976-Fluoro-N-{(3S)-1-[(1S)-1-methyl-2-oxo2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1508] Mass spectrum: Found: MH⁺ 448 H.p.l.c. (1) Rt 3.03 min

Example 1985-Isoxazol-3-yl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1509] Mass spectrum: Found: MH⁺ 453 H.p.l.c. (1) Rt 2.84 min

Example 1995-(5-Chloro-1,3,4-thiadiazol-2-yl)-N-{(3S)-1-[(1R)-1-methyl-2oxo-2-piperidin-1-ylethyl}-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1510] Mass spectrum: Found: MH⁺ 504 H.p.l.c. (1) Rt 3.06 min

Example 2006-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-pieridin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulphonamide

[1511] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.27 min

Example 2015′-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1512] Mass spectrum: Found: MH⁺ 502 H.p.l.c. (1) Rt 3.46 min

Example 202N-{(3S)-1-[(1R)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thieno[2,3-c]pyridine-2-sulfonamide

[1513] Mass spectrum: Found: MH⁺ 437 H.p.l.c. (1) Rt 2.49 min

Example 203(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1514] Mass spectrum: Found: MH⁺ 440 H.p.l.c. (1) Rt 3.14 min

Example 2045-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1515] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.28 min

Example 2053-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}isoquinoline-7-sulfonamide

[1516] Mass spectrum: Found: MH⁺ 465 H.p.l.c. (1) Rt 2.90 min

Example 2064-Methoxy-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}benzenesulfonamide

[1517] Mass spectrum: Found: MH⁺ 409 H.p.l.c. (1) Rt 2.74 min

Example 2073-Chloro-N-{(3S)-1-[(1S)-1-methyl-2oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}isoquinoline-7-sulfonamide

[1518] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 2.95 min

Example 208N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-5-pyridin-2-ylthiophene-2-sulfonamide

[1519] Mass spectrum: Found: MH⁺ 463 H.p.l.c. (1) Rt 2.79 min

Example 209N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-3-(1H-tetraazol-5-yl)benzenesulfonamide

[1520] Mass spectrum: Found: MH⁺ 448 H.p.l.c. (1) Rt 2.66 min

Example 210N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1521] Mass spectrum: Found: MH⁺ 430 H.p.l.c. (1) Rt 2.97 min

Example 211N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1522] Mass spectrum: Found: MH⁺ 436 H.p.l.c. (1) Rt 2.99 min

Example 2124-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1523] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.19 min

Example 213N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-5-(1,2,3-thiadiazol-4-yl)thiophene-2-sulfonamide

[1524] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 2.8 min

Example 2144-Methoxy-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl-2-oxopyrrolidin-3-yl}benzenesulfonamide

[1525] Mass spectrum: Found: MH⁺ 410 H.p.l.c. (1) Rt 2.7 min

Example 2154′-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1,1′-biphenyl-4-sulfonamide

[1526] Mass spectrum: Found: MH⁺ 490 H.p.l.c. (1) Rt 3.42 min

Example 2164-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}benzenesulfonamide

[1527] Mass spectrum: Found: MH⁺ 414 H.p.l.c. (1) Rt 2.91 min

Example 2176-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamidecompound with4-chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1528] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.28 min

Example 218(E)-2-(4-Chlorophenyl)-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1529] Mass spectrum: Found: MH⁺ 440 H.p.l.c. (1) Rt 3.14 min

Example 2196-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-1-yl}-1H-benzimidazole-2-sulfonamide

[1530] Mass spectrum: Found: MH⁺ 454 H.p.l.c. (1) Rt 2.55 min

Example 2205-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1531] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.29 min

Example 2215′-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1532] Mass spectrum: Found: MH⁺ 502 H.p.l.c. (1) Rt 3.46 min

Example 2223-Chloro-N-{(3R)-1-[(1R)-1-methyl-2oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}isoquinoline-7-sulfonamide

[1533] Mass spectrum: Found: MH⁺ 469 H.p.l.c. (1) Rt 3.37 min

Example 2235-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1534] Mass spectrum: Found: MH⁺ 470 H.p.l.c. (1) Rt 3.19 min

Example 2245-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1535] Mass spectrum: Found: MH⁺ 469 H.p.l.c. (1) Rt 3.37 min

Example 2253-Chloro-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}isoquinoline-7-sulfonamide

[1536] Mass spectrum: Found: MH⁺ 465 H.p.l.c. (1) Rt 2.87 min

Example 2266-Fluoro-N-{(3S)-1[-(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1537] Mass spectrum: Found: MH⁺ 448 H.p.l.c. (1) Rt 2.4 min

Example 2275-Chloro-3-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1538] Mass spectrum: Found: MH⁺ 484 H.p.l.c. (1) Rt 3.38 min

Example 2286-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1539] A solution of6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide(0.015 g) in THF (0.5 ml) was treated with diisopropyl azodicarboxylate(0.01 ml), 3-furanmethanol (0.004 ml) and tri-n-butylphosphine (0.008ml) and shaken at room temperature for 60 h. The mixture wasconcentrated under reduced pressure and the residue purified by massdirected preparative h.p.l.c. to give the title compound (0.015 g) as acolourless gum.

[1540] Mass spectrum: Found: MH⁺ 546 H.p.l.c. (1) Rt 3.33 min

[1541] Using similar chemistry, the following were prepared:

Example 2296-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamideformate

[1542] The title compound was isolated from a crude reaction mixtureusing mass directed preparative h.p.l.c.

[1543] Mass spectrum: Found: MH⁺ 557 H.p.l.c. (1) Rt 2.9 min

Example 2306-Chloro-N-ethyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1544] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.32 min

Example 231N-{1-[(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}benzamide

[1545] A solution of tert-butyl(2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino)-2-oxopyrrolidin-1-1-yl)propanoate(0.025 g) in DCM (1 ml) was treated with trifluoroacetic acid (1 ml) andstirred at room temperature for 2 h. The mixture was then concentratedunder reduced pressure to give an oil which was subsequently treatedwith 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.013 g), HOBT (0.009 g) and triethylamine (0.023 ml). After stirringat room temperature for 1 h, N-piperidin-3-ylbenzamide (0.015 g) wasadded and stirring was continued for 48 h. The reaction mixture waspartitioned between DCM and water. The organic extract was concentratedunder reduced pressure and the residue purified using SPE (silica,eluting with cyclohexane:ethyl acetate 5:1, 3:1, 1:1, 1:3 and ethylacetate) to give the title compound (0.012 g) as a colourless gum.

[1546] Mass spectrum: Found: MH⁺ 583 H.p.l.c. (1) Rt 3.32 min

Example 2326-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide

[1547] To a solution of(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid (0.035 g) in DCM (2 ml) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.044 g),HOBT (0.031 g) and triethylamine (0.064 ml) and the mixture was stirredat room temperature for 30 min. Morpholine (0.02 ml) was added and theresultant mixture stirred at room temperature for 16 h. The mixture waspartitioned between DCM and water. The aqueous layer was re-extractedwith DCM and the combined, dried (over magnesium sulphate) organicextracts were concentrated under reduced pressure. The residue waspurified using mass directed preparative h.p.l.c. to give the titlecompound (0.008 g) as a white solid.

[1548] Mass spectrum: Found: MH⁺ 536 H.p.l.c. (1) Rt 3.20 min

[1549] Using similar chemistry, the following were prepared:

Example 233N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1550] The title compound was prepared from Intermediate 49

[1551] Mass spectrum: Found: MH⁺ 523 H.p.l.c. (1) Rt 2.87 min

Example 2346-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1552] The title compound was prepared from Intermediate 63

[1553] Mass spectrum: Found: MH⁺ 546 H.p.l.c. (1) Rt 3.33 min

Example 2356-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide

[1554] The title compound was prepared from Intermediate 62.

[1555] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 3.18 min

Example 236N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo-1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1556] The title compound was prepared from Intermediate 49.

[1557] Mass spectrum: Found: MH⁺ 550 H.p.l.c. (1) Rt 2.66 min

Example 237N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-diazepan-1-yl)-2oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1558] The title compound was prepared from Intermediate 49.

[1559] Mass spectrum: Found: MH⁺ 564 H.p.l.c. (1) Rt 2.7 min

Example 238N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1560] The title compound was prepared from Intermediate 49.

[1561] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (3).Rt 10.85 min

Example 239N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1562] The title compound was prepared from Intermediate 49.

[1563] Mass spectrum: Found: MH⁺ 598 H.p.l.c. (3) Rt 11.3 min

Example 240N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1564] The title compound was prepared from Intermediate 49.

[1565] Mass spectrum: Found: MH⁺ 584 H.p.l.c. (3) Rt 10.7 min

Example 241N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(1S,4S)-2,5-diazabicyclo[2,2,1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide

[1566] The title compound was prepared from Intermediate 49.

[1567] Mass spectrum: Found: MH⁺ 534 H.p.l.c. (1) Rt 2.37 min

Example 242N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-[(1S)-1-methyl-2-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-oxoethyl]-2-oxopyrrolidin-3-yl)glycinamidehydrobromide

[1568] The title compound was prepared from Intermediate 49.

[1569] Mass spectrum: Found: MH⁺ 548 H.p.l.c. (3) Rt 10.3 min

Example 243N2-[(6-Chloro-2-naphthyl)sulfonyl]-1-N2-(3S)-1-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1570] The title compound was prepared from Intermediate 49.

[1571] Mass spectrum: Found: MH⁺ 550 H.p.l.c. (3) Rt 10.4 min

Example 244N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-2-(1,4-diazepan-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1572] The title compound was prepared from Intermediate 49.

[1573] Mass spectrum: Found: MH⁺ 536 H.p.l.c. (3) Rt 14.5 min

Example 245N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-[(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide

[1574] The title compound was prepared from Intermediate 49.

[1575] Mass spectrum: Found: MH⁺ 551 H.p.l.c. (3) Rt 13.4 min

Example 246N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-((1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5yl]-2-oxoethyl]-2-oxopyrrolidin-3-yl)glycinamide

[1576] The title compound was prepared from Intermediate 49.

[1577] Mass spectrum: Found: MH⁺ 535 H.p.l.c. (3) Rt 12.7 min

Example 2476-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide

[1578] The title compound was prepared from Intermediate 95.

[1579] Mass spectrum: Found: MH⁺ 577 H.p.l.c. (1) Rt 3.24 min

Example 2486-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamideformate

[1580] The title compound was prepared from Intermediate 97.

[1581] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 3.62 min

Example 2496-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate

[1582] The title compound was prepared from Intermediate 96.

[1583] Mass spectrum: Found: MH⁺ 557 H.p.l.c. (1) Rt 2.83 min

Example 2506-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamideformate

[1584] The title compound was prepared from Intermediate 95.

[1585] Mass spectrum: Found: MH⁺ 644 H.p.l.c. (1) Rt 2.83 min

Example 2516-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-yl]methyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate

[1586] The title compound was prepared from Intermediate 96.

[1587] Mass spectrum: Found: MH⁺ 624 H.p.l.c. (1) Rt 2.74 min

Example 252 MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate

[1588] A solution of5′-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5sulfonamide(0.025 g) in THF (3 ml) was cooled to −78° C. under nitrogen, andtreated with lithium bis(trimethylsilyl) amide (1.0M solution in THF;0.092 ml), followed by methyl bromoacetate (0.026 ml). The resultantsolution was allowed to reach room temperature and stirred for a further22 h. Methanol was added and the mixture was concentrated under reducedpressure. The residue was partitioned between DCM and water and thenpassed through a hydrophobic frit. The organic extract was concentratedunder reduced pressure and the residue purified by mass directedpreparative h.p.l.c. to give the title compound (0.006 g) as a whitesolid.

[1589] Mass spectrum: Found: MH⁺ 574 H.p.l.c. (1) Rt 3.57 min

[1590] Similarly prepared using the commercially available alkyl halide,was:

Example 2535′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1591] Mass spectrum: Found: MH⁺ 541 H.p.l.c. (1) Rt 3.56 min

Example 254N-[(5′-Chloro-2,2′-bithien-5yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine

[1592] Using standard alkaline hydrolysis conditions, the title compoundwas prepared from Example 252.

[1593] Mass spectrum: Found: MH⁺ 560 H.p.l.c. (1) Rt 3.47 min

Example 2556-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1594] To a solution of(2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (0.018 g) in DCM (0.5 ml) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.018 g),HOBT (0.013 g) and triethylamine (0.039 ml) and the mixture was stirredat room temperature for 75 min. 3-Methylpiperidine(0.010 ml) was addedand the resultant mixture stirred at room temperature for 48 h. Themixture was partitioned between DCM and saturated sodium bicarbonatesolution and then passed through a hydrophobic frit. The organic extractconcentrated under reduced pressure and the residue was purified usingSPE (silica, eluting with cyclohexane:ethyl acetate 2:1, 1:1; ethylacetate; ethyl acetate:methanol 2:1, 1:1) to give the title compound(0.007 g) as a white solid.

[1595] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.4 min

[1596] Using similar chemistry, the following were prepared:

Example 256N-{1-[(2R)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)pronanoyl]piperidin-3-yl}acetamide

[1597] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 3.14 min

Example 2576-Chloro-N-((3S)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1598] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.36 min

Example 2586-Chloro-N-((3S)-1-{(1R)-1-methyl-2-[(2S)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1599] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.36 min

Example 2596-Chloro-N-[(3S)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1600] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.59 min

Example 2606-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1601] Mass spectrum: Found: MH⁺ 450 H.p.l.c. (1) Rt 3.03 min

Example 2616-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1602] Mass spectrum: Found: MH⁺ 466 H.p.l.c. (1) Rt 2.95 min

Example 2626-Chloro-N-((3S)-1-{(1R)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1603] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 2.98 min

Example 2636-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1604] Using Intermediate 30 and piperidine, and the chemistry describedfor Example 255, the title compound was prepared.

[1605] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.4 min

Example 2646-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1606] Using Intermediate 55 and 3-methylpiperidine and chemistrydescribed for Example 255, the title compound was prepared.

[1607] Mass spectrum: Found: MH⁺ 494 H.p.l.c. (1) Rt 3.03 min

[1608] Using similar chemistry, the following were prepared:

Example 265N-[1-((2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]acetamide

[1609] Mass spectrum: Found: MH⁺ 535 H.p.l.c. (1) Rt 3.1 min

Example 2666-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-(3-}[(phenylsulfonyl)amino]methyl}piperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1610] Mass spectrum: Found: MH⁺ 647 H.p.l.c. (1) Rt 3.55 min

Example 2676-Chloro-N-((3S)-1-{(1R)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide

[1611] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.1 min

Example 2686-Chloro-N-((3S)-1-{(1R)-2-[2-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide

[1612] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.23 min

Example 2696-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1613] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.49 min

Example 270N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide

[1614] Mass spectrum: Found: MH⁺ 597 H.p.l.c. (1) Rt 3.41 min

Example 2716-Chloro-N-[(3S)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sulfonamide

[1615] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 2.65 min

Example 2726-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1616] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.21 min

Example 2736-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-[(2S)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1617] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.49 min

Example 274N-{(3S)-1-[(1R)-2-Azepan-1-yl-1-methyl-2oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloro-N-methylnaphthalene-2-sulfonamide

[1618] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.41 min

Example 2756-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-(4pyrrolidin-1-ylpiperidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1619] Mass spectrum: Found: MH⁺ 547 H.p.l.c. (1) Rt 2.68 min

Example 2766-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)piperidin-1-yl}ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1620] Mass spectrum: Found: MH⁺ 561 H.p.l.c. (1) Rt 2.77 min

Example 2776-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(4-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1621] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.58 min

Example 278N-{(3S)-1-[(1R)-2-(4-{[(Benzylsulfonyl)amino]methyl}piperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloro-N-methylnaphthalene-2-sulfonamide

[1622] Mass spectrum: Found: MH⁺ 661 H.p.l.c. (1) Rt 3.52 min

Example 279N-{1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-4-yl]benzamide

[1623] Mass spectrum: Found: MH⁺ 597 H.p.l.c. (1) Rt 3.38 min

Example 280N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)pyrrolidin-3-yl]benzamide

[1624] Mass spectrum: Found: MH⁺ 583 H.p.l.c. (1) Rt 3.32 min

Example 281N-{[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-2-yl]methyl}benzamide

[1625] Mass spectrum: Found: MH⁺ 611 H.p.l.c. (1) Rt 3.52 min

Example 282N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-4-yl]acetamide

[1626] Mass spectrum: Found: MH⁺ 535 H.p.l.c. (1) Rt 3.04 min

Example 283N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)pyrrolidin-3-yl]acetamide

[1627] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 2.99 min

Example 2846-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylcarbonyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1628] Mass spectrum: Found: MH⁺ 575 H.p.l.c. (1) Rt 3.42 min

Example 2856-Chloro-N-((3S)-1-{(1R)-2-[4(dimethylamino)piperidin-1-yl]-1-methyl-2-oxoethyl-}2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide

[1629] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 2.65 min

Example 2866-Chloro-N-((3S)-1-{(1R)-2-[4-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-N-methylnaphthalene-2-sulfonamide

[1630] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.11 min

Example 2876-Chloro-N-{(3S)-1-[(1R)-2-(4-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-methylnaphthalene-2-sulfonamide

[1631] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.29 min

Example 2886-Chloro-N-{(3S)-1-[(1R)-2-(3-methoxypiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-methylnaphthalene-2-sulfonamide

[1632] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.35 min

Example 2896-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1633] Mass spectrum: Found: MH⁺ 479 H.p.l.c. (1) Rt 3.18 min

Example 2906-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1634] The title compound was prepared from Intermediate 30.

[1635] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.25 min

Example 2916-Chloro-N-methyl-N-((3R)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1636] The title compound was prepared from Intermediate 30.

[1637] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.51 min

Example 2926-Chloro-N-[(3R)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sulfonamide

[1638] The title compound was prepared from Intermediate 30.

[1639] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 2.82 min

Example 2936-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1640] A solution of6-chloro-N-{(3S)-1-[(1S)-1l-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide(0.01 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treatedwith lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.026 ml),followed by bromoacetonitrile (0.013 g). The resultant solution wasallowed to reach room temperature and stirred for a further 16 h. Themixture was then cooled to −78° C. and further lithiumbis(trimethylsilyl) amide (0.026 ml) added. After reaching roomtemperature, the reaction mixture was stirred for a further 18 h andthen quenched by the addition of methanol (1 ml). The resultant solutionwas concentrated under reduced pressure and the residue purified by massdirected preparative h.p.l.c. to give the title compound (0.003 g) as awhite solid.

[1641] Mass spectrum: Found: MH⁺ 505 H.p.l.c. (1) Rt 3.16 min

[1642] Similarly prepared using commercially available alkyl halides,were:

Example 2946-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1643] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 3.11 min

Example 2956-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1644] Mass spectrum: Found: MH⁺ 564 H.p.l.c. (1) Rt 3.39 min

Example 296N2-[(6-Chloro-2-naphthyl)sulfonyl]-N1-methyl-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1645] Mass spectrum: Found: MH⁺ 537 H.p.l.c. (1) Rt 2.98 min

Example 297N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1646] Mass spectrum: Found: MH⁺ 506 H.p.l.c. (1) Rt 3.26 min

Example 298 MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate

[1647] Mass spectrum: Found: MH⁺ 538 H.p.l.c. (1) Rt 3.12 min

Example 299 EthylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate

[1648] Mass spectrum: Found: MH⁺ 552 H.p.l.c. (1) Rt 3.36 min

Example 300 tert-ButylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate

[1649] Mass spectrum: Found: MH⁺ 580 H.p.l.c. (1) Rt 3.45 min

Example 301N-[1-((2R)-2-{(3R)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide

[1650] Using Example 327 and the synthetic procedure described forIntermediate 52, the title compound was prepared.

[1651] Mass spectrum: Found: MH⁺ 597 H.p.l.c. (1) Rt 3.37 min

Example 302N-{(3R)-1-[(1R)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloro-N-methylnaphthalene-2-sulfonamide

[1652] Using Example 328 and the synthetic procedure described forIntermediate 52, the title compound was prepared.

[1653] Mass spectrum: Found: MH⁺ 491 H.p.l.c. (1) Rt 3.4 min

Example 303N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine

[1654] To a solution of methylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate(0.010 g) in THF (2 ml) was added lithium hydroxide (0.003 g) in water(2 ml), and the resultant solution stirred for 16 h. The mixture wasacidified to pH5 using hydrochloric acid (2N), and then concentratedunder reduced pressure. The residue was purified using mass directedpreparative h.p.l.c. to give the title compound (0.006 g) as a whitesolid.

[1655] Mass spectrum: Found: MH⁺ 524 H.p.l.c. (1) Rt 3.00 min

Example 3041-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidine-2-carboxylicacid

[1656] To a solution of(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (0.025 g) in DCM (10 ml) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036 g),HOBT (0.026 g) and triethylamine (0.026 ml) and the mixture was stirredat room temperature for 30 min. Ethyl pipecolinate (0.030 g) was addedand the resultant mixture stirred at room temperature for 16 h. Themixture was partitioned between DCM and water. The aqueous layer wasre-extracted with DCM and the combined, dried (over magnesium sulphate)organic extracts were concentrated under reduced pressure. The residuewas then dissolved in a mixture of THF (1 ml) and water (1 ml), treatedwith lithium hydroxide (0.005 g) and stirred at room temperature for 18h. The reaction mixture was acidified to pH5 using hydrochloric acid(2N) and concentrated under reduced pressure. The residue was purifiedusing SPE (aminopropyl stationary phase, washed with methanol and elutedwith 10% hydrochloric acid in methanol) to give the title compound(0.007 g) as white solid.

[1657] Mass spectrum: Found: MH⁺ 508 H.p.l.c. (1) Rt 3.09 min

Example 3056-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1658] A solution of tert-butyl(2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate(0.025 g) in DCM (3 ml) was treated with trifluoroacetic acid (3 ml) andstirred at room temperature for 2 h. The mixture was then concentratedunder reduced pressure to give an oil which was subsequently treatedwith 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride(0.013 g), HOBT (0.009 g) and triethylamine (0.023 ml). After stirringat room temperature for 1 h, piperidine (0.007 ml) was added andstirring was continued for 48 h. The reaction mixture was partitionedbetween DCM and water. The organic extract was concentrated underreduced pressure and the residue purified using SPE (silica, elutingwith cyclohexane:ethyl acetate 5:1, 3:1, 1:1, 1:3 and ethyl acetate) togive the title compound (0.021 g) as a colourless gum.

[1659] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.27 min

Example 3066-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1660] To a solution of(2S)-2{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid (0.020 g) in DCM (2 ml) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.011 g),HOBT (0.007 g) and triethylamine (0.020 ml) and the mixture was stirredat room temperature for 30 min. Piperidine (0.006 ml) was added and theresultant mixture stirred at room temperature for 16 h. The mixture waspartitioned between DCM and water. The aqueous layer was re-extractedwith DCM and the combined, dried (over magnesium sulphate) organicextracts were concentrated under reduced pressure. The residue waspurified using mass directed preparative h.p.l.c. to give the titlecompound (0.002 g) as a colourless gum.

[1661] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.51 min

[1662] Using similar chemistry, the following were prepared:

Example 3076-Chloro-N-methyl-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1663] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt3.61 min

Example 3086-Chloro-N-[(3S)-1-((1S)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sulfonamide

[1664] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 2.88 min

Example 3096-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1665] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.48 min

Example 310 MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate

[1666] To a solution of(2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-methoxy-2-oxoethyl)amino]-2-oxopyrrolidin-1-yl}propanoicacid (0.032 g) in DCM (5 ml) were added1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.02 g),HOBT (0.014 g) and triethylamine (0.034 ml) and the mixture was stirredat room temperature for 1 h. Piperidine (0.01 ml) was added and theresultant mixture stirred at room temperature for 72 h. The mixture wasconcentrated under reduced pressure and the residue purified using massdirected preparative h.p.l.c. to give the title compound (0.017 g) as awhite solid.

[1667] Mass spectrum: Found: MH⁺ 536 H.p.l.c. (1) Rt 3.54 min

Example 311N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine

[1668] To a solution of methylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate(0.010 g) in THF (1 ml) was added lithium hydroxide (0.005 g) in water(1 ml), and the resultant solution stirred for 16 h. The mixture wasacidified to pH5 using hydrochloric acid (2N), and then concentratedunder reduced pressure. The residue was purified using SPE (eluting withmethanol and then 10% HCl/methanol) to give the title compound (0.01 g)as a white solid.

[1669] Mass spectrum: Found: MH⁺ 522 H.p.l.c. (1) Rt 3.29 min

Example 3126-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1670] A solution of6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide(0.015 g) in THF (2 ml) was cooled to −78° C. under nitrogen, andtreated with lithium bis(trimethylsilyl) amide (1.0M solution in THF;0.042 ml), followed by bromoacetonitrile (0.019 g). The resultantsolution was allowed to reach room temperature and stirred for a further16 h. The mixture was then cooled to −78° C. and further lithiumbis(trimethylsilyl) amide (0.042 ml) added. After reaching roomtemperature, the reaction mixture was stirred for a further 18 h andthen quenched by the addition of methanol (1 ml). The resultant solutionwas concentrated under reduced pressure and the residue partitionedbetween water and DCM. The organic layer was separated, dried (overmagnesium sulphate) and concentrated under reduced pressure. The residuewas purified by mass directed preparative h.p.l.c to give the titlecompound (0.007 g) as a colourless gum.

[1671] Mass spectrum: Found: MH⁺ 503 H.p.l.c. (1) Rt 3.35 min

[1672] Similarly prepared using commercially available alkyl halides,were:

Example 313N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1673] Mass spectrum: Found: MH⁺ 521 H.p.l.c. (1) Rt 3.07 min

Example 3146-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide

[1674] Mass spectrum: Found: MH⁺ 534 H.p.l.c. (1) Rt 3.39 min

Example 315 and Example 316N-Allyl-6-chloro-N-{1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide[Isomer 1 and Isomer 2]

[1675] The title compounds were prepared by alkylation of Example 2 withallyl iodide, followed by purification using mass directed preparativeh.p.l.c.

[1676] Isomer 1 Mass spectrum: Found: MH⁺ 504 H.p.l.c. (1) Rt 3.5 min

[1677] Isomer 1 Mass spectrum: Found: MH⁺ 504 H.p.l.c. (1) Rt 3.52 min

Example 317N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinamide

[1678] A solution of6-chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide(0.01 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treatedwith lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.023 ml),followed by 2-bromoacteamide (0.012 g). The resultant solution wasallowed to reach room temperature and stirred for a further 16 h. Themixture was then cooled to −78° C. and further lithiumbis(trimethylsilyl) amide (0.023 ml) added. After reaching roomtemperature, the reaction mixture was stirred for a further 16 h andthen quenched by the addition of methanol (1 ml). The resultant solutionwas concentrated under reduced pressure and the residue partitionedbetween water and DCM. The organic layer was separated, dried (overmagnesium sulphate) and concentrated under reduced pressure. The residuewas purified by mass directed preparative h.p.l.c. to give the titlecompound (0.001 g) as a white solid.

[1679] Mass spectrum: Found: MH⁺ 590 H.p.l.c. (1) Rt 2.77 min

[1680] Similarly prepared using commercially available alkyl halides,were:

Example 318 MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1l-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate

[1681] Mass spectrum: Found: MH⁺ 605 H.p.l.c. (1) Rt 2.62 min

Example 3196-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)naphthalene-2-sulfonamide

[1682] Mass spectrum: Found: MH⁺ 603 H.p.l.c. (1) Rt 2.81 min

Example 320 and Example 321N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate [Isomer 1 and Isomer 2]

[1683] The title compounds were prepared by alkaline hydrolysis (LiOH)of Example 318, followed by purification using mass directed preparativeh.p.l.c..

[1684] Isomer 1 Mass spectrum: Found: MH⁺ 591 H.p.l.c. (1) Rt 2.6 min

[1685] Isomer 1 Mass spectrum: Found: MH⁺ 591 H.p.l.c. (1) Rt 2.63 min

Example 322N-[(6-Chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycine

[1686] The title compound was prepared by trifluoroacetic acidhydrolysis of Intermediate 88, followed by purification using massdirected preparative h.p.l.c..

[1687] Mass spectrum: Found: MH⁺ 591 H.p.l.c. (1) Rt 2.85 min

Example 323N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide

[1688] A solution of tert-butyl(2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate(0.017 g) in DCM (0.5 ml) was treated with trifluoroacetic acid (0.5 ml)and stirred at room temperature for 2 h. The mixture was thenconcentrated under reduced pressure to give an oil which wassubsequently treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.01 g),HOBT (0.007 g) and triethylamine (0.020 ml). After stirring at roomtemperature for 1 h, N-piperidin-3-ylbenzamide (0.010 g) was added andstirring was continued for 16 h. The reaction mixture was partitionedbetween DCM and water. The organic extract was concentrated underreduced pressure and the residue purified using SPE (silica, elutingwith cyclohexane:ethyl acetate 3:1, 1:1, 1:3, ethyl acetate) to give thetitle compound (0.012 g) as a pale yellow gum.

[1689] Mass spectrum: Found: MH⁺ 597 H.p.l.c. (1) Rt 3.35 min Note:Example 323=Example 270.

[1690] Using the procedure described above, the following compounds werealso prepared:

Example 3246-Chloro-N-methyl-N-((3S)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1691] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.57 min

Example 325N-((3S)-1-{(1R)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloro-N-methylnaphthalene-2-sulfonamide

[1692] Mass spectrum: Found: MH⁺ 490 H.p.l.c. (1) Rt 3.18 min

Example 3266-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1693] Using Intermediate 32 and the procedure described for Example 1,the title compound was prepared.

[1694] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.35 min

[1695] Using similar chemistry, the following were prepared:

Example 327N-{1-[(2R)-2-((3R)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}benzamide(two diastereoisomers)

[1696] Mass spectrum: Found: MH⁺ 583 H.p.l.c. (1) Rt 3.26 & 3.44 min

Example 328N-{(3R)-1-[(1R)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1697] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.29 min

Example 3296-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1698] Mass spectrum: Found: MH⁺ 466 H.p.l.c. (1) Rt 2.95 min

Example 3306-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1699] Mass spectrum: Found: MH⁺ 450 H.p.l.c. (1) Rt 3.05 min

Example 3316-Chloro-N-((3R)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1700] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.29 min

Example 3326-Chloro-N-((3R)-1-{(1R)-1-methyl-2-[(2S)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1701] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.29 min

Example 3336-Chloro-N-[(3R)-1-((1R)-2-{-2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1702] Mass spectrum: Found: MH⁺ 549 H.p.l.c. (1) Rt 2.66 min

Example 334N-((3R)-1-{(1R)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide

[1703] Mass spectrum: Found: MH⁺ 476 H.p.l.c. (1) Rt 3.15 min

Example 3356-Chloro-N-{1-[(1R)-1-methyl-2-(4-methylpiperazin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1704] Using Intermediate 37, and the synthetic procedure described forExample 1, the title compound was prepared.

[1705] Mass spectrum: Found: MH⁺ 479 H.p.l.c. (1) Rt 2.92 min

[1706] Using similar chemistry, the following were prepared:

Example 3366-Bromo-N-{1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1707] The title compound was prepared using Intermediate 119.

[1708] Mass spectrum: Found: MH⁺ 509 H.p.l.c. (1) Rt 3.26 min

Example 3375-Chloro-3-methyl-N-{1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1709] The title compound was prepared using Intermediate 120.

[1710] Mass spectrum: Found: MH⁺ 484 H.p.l.c. (1) Rt 3.31 min

Example 3383-Chloro-N-{1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}isoquinoline-7-sulfonamide

[1711] Using Intermediate 40, and the synthetic procedure described forExample 1, the title compound was prepared.

[1712] Mass spectrum: Found: MH⁺ 465 H.p.l.c. (1) Rt 2.84 min

Example 3393′-Chloro-N-{1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1,1′-biphenyl-4-sulfonamide

[1713] Using Intermediate 39, and the synthetic procedure described forExample 1, the title compound was prepared.

[1714] Mass spectrum: Found: MH⁺ 490 H.p.l.c. (1) Rt 3.34 min

Example 3407-Hydroxy-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1715] n-Butylamine (1 ml) was added to a suspension of Intermediate 51(0.015 g) in dry THF (1 ml), stirred at room temperature for 5 h andconcentrated under reduced pressure. The residue was partitioned betweenDCM and water. The separated organic extract was passed through ahydrophobic frit and the filtrate concentrated under reduced pressure togive the title compound (0.0035 g) as an oil.

[1716] Mass spectrum: Found: MH⁺ 446 H.p.l.c. (1) Rt 3.05 min

Example 3416-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1717] Using Intermediate 56 and the procedure described for Example 1,the title compound was prepared.

[1718] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.49 min

[1719] Using similar chemistry, the following were prepared:

Example 3426-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1720] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.25 min

Example 3436-Chloro-N-[(3R)-1-((1R)-2-{2-[(diethylamino)methyl]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]-N-methylnaphthalene-2-sulfonamide

[1721] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 2.74 min

Example 344N-((3R)-1-{(1R)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloro-N-methylnaphthalene-2-sulfonamide

[1722] Mass spectrum: Found: MH⁺ 490 H.p.l.c. (1) Rt 3.29 min

Example 3456-Chloro-N-methyl-N-((3R)-1-{(1R)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1723] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.43 min

Example 3466-Chloro-N-((3S)-1-{(1S)-2-[3-(ethylamino)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1724] To a solution of acetaldehyde (0.041 ml from a stock solutionmade up from 0.01271 acetaldehyde dissolved in 1 ml DCM)) in dry DCM(0.4 ml) treated with acetic acid (0.1 ml from a stock solution made upfrom 0.0054 ml acetic acid dissolved in 1 ml DCM) was addedN-{(3S)-1-[(1S)-2-(3-aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide [Example 365] (0.045 g) followed bytetraethylammonium triacetoxyborohydride (0.005 g). The mixture wasstirred at room temperature, under nitrogen, for 60 h. DCM (1 ml) wasadded and the resultant solution washed with saturated sodiumbicarbonate (1 ml) in a hydrophobic frit. The solvent was concentratedunder reduced pressure and the residue purified by mass directedpreparative h.p.l.c. to give the title compound (0.8 mg) as an oil.

[1725] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (2) Rt 6.22 min

[1726] Similarly prepared using commercially available aldehydes, were:

Example 3476-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrrol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1727] Mass spectrum: Found: MH⁺ 558 H.p.l.c. (2) Rt 5.21 min

Example 3486-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1728] Mass spectrum: Found: MH⁺ 570 H.p.l.c. (2) Rt 5.18 min

Example 3496-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxybutyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1729] Mass spectrum: Found: MH⁺ 551 H.p.l.c. (2) Rt 6.9 min

Example 3506-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-4-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1730] Mass spectrum: Found: MH⁺ 570 H.p.l.c. (2) Rt 5.76 min

Example 351N-{(3S)-1-[(1S)-2-(3-{[(2-Aminopyrimidin-5-yl)methyl]amino}piperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide

[1731] Mass spectrum: Found: MH⁺ 586 H.p.l.c. (2) Rt 6.42 min

Example 3526-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1732] Mass spectrum: Found: MH⁺ 570 H.p.l.c. (2) Rt 5.89 min

Example 3536-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrazol-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1733] Mass spectrum: Found: MH⁺ 559 H.p.l.c. (2) Rt 7.3 min

Example 3546-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-4-ylmethyl)amino]piperidin-1-}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1734] Mass spectrum: Found: MH⁺ 570 H.p.l.c. (2) Rt 5.69 min

Example 3556-Chloro-N-((3S)-1-{(1S)-2-[3-({[5-(hydroxymethyl)-2-furyl]methyl}amino)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1735] Mass spectrum: Found: MH⁺ 589 H.p.l.c. (2) Rt 7.1 min

Example 3566-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1,3-thiazol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1736] Mass spectrum: Found: MH⁺ 576 H.p.l.c. (2) Rt 5.89 min

Example 3576-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-{[(1-methyl-1H-imidazol-2-yl)methyl]amino}piperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1737] Mass spectrum: Found: MH⁺ 573 H.p.l.c. (2) Rt 4.22 min

Example 3586-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1738] Mass spectrum: Found: MH⁺ 565 H.p.l.c. (2) Rt 7.4 min

Example 3596-Chloro-N-[(3S)-1-((1S)-2-{3-[(1H-imidazol-4-ylmethyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1739] Mass spectrum: Found: MH⁺ 559 H.p.l.c. (2) Rt 9.42 min

Example 3606-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-ethoxy-2-oxopropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1740] Mass spectrum: Found: MH⁺ 581 H.p.l.c. (2) Rt 6.21 min

Example 3616-Chloro-N-[(3S)-1-((1S)-2-{3-[(3-methoxypropyl)amino]piperidin-1-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1741] Mass spectrum: Found: MH⁺ 551 H.p.l.c. (2) Rt 7.75 min

Example 3624-[({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)methyl]-1-methylpyridiniumiodide

[1742] Mass spectrum: Found: MH⁺ 588 H.p.l.c. (2) Rt 4.75 min

Example 3636-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-{[(5-methyl-1H-imidazol-4-yl)methyl]amino}piperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1743] Mass spectrum: Found: MH⁺ 573 H.p.l.c. (2) Rt 5.03 min

Example 364 Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate

[1744] A solution of(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (0.408 g) in DCM (21 ml) was treated with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.394 g),HOBT (0.278 g) and triethylamine (0.286 ml) and stirred at roomtemperature for 1 h. A solution of benzyl (3S)-piperidin-3-ylcarbamate(0.361 g) in DCM (1 ml) was then added and stirring continued for 72 h.The mixture was partitioned between DCM and water. The separated organicextracts were washed with water and brine, dried (over magnesiumsulphate), and concentrated under reduced pressure. The residue waspurified using Biotage™ chromatography (eluting with hexane:ethylacetate 1:7→1:10) to give the title compound (0.268 g) as an oil.

[1745] Mass spectrum: Found: MH⁺ 613 H.p.l.c. (1) Rt 3.59 min

Example 365N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide

[1746] Benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate(0.128 g) was dissolved in DCM (3.5 ml) and treated with trifluoroaceticacid (10.5 ml) and stirred at room temperature for 6 h. The mixture wasconcentrated under reduced pressure and the residue purified by SPE(acid ion-exchange, eluting with ethyl acetate:methanol 9:1) to give thetitle compound (0.093 g) as a colourless oil.

[1747] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 2.75 min

Example 366N-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide

[1748] Using benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamateand the synthetic procedure described for Example 365, the titlecompound was prepared.

[1749] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 2.55 min

Example 3675-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(1-piperidinyl)ethyl]-2-oxopyrrolidinyl}-2-thiophenesulfonamide

[1750] A mixture of5-bromo-N-[2-methoxy-4-(2-polystyrylethoxy)benzyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(1-piperidinyl)ethyl]-2-oxopyrrolidinyl}-2-thiophenesulfonamide(0.025 g), sodium carbonate (0.0017 g), 4-chlorobenzeneboronic acid(0.0042 g), tetrakis(triphenyphosphine) palladium(0) (0.0015 g) andtetrahydrofuran-water (4:1, 0.5 ml) was stirred gently at in a sealedvessel at 78° C. for 72 h. The resin was filtered, washed with DMF, 0.2NHCl, methanol and then DCM. The dried resin was then treated withtrifluoroacetic acid-DCM (1:1, 0.5 ml), shaken at room temperature for 1h and filtered. The resultant filtrate was concentrated under reducedpressure to give the title compound (0.0026 g) as an off-white glass.

[1751] Mass spectrum: Found: MH⁺ 496 H.p.l.c. (1) Rt 3.39 min

[1752] Using similar chemistry, the following were prepared:

Example 368N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-5-phenylthiophene-2-sulfonamide

[1753] Mass spectrum: Found: MH⁺ 462 H.p.l.c. (1) Rt 3.2 min

Example 3695-(4-Hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1754] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 2.98 min

Example 3705-(3-Methoxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1755] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.23 min

Example 371N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-5-(4-methylphenyl)thiophene-2-sulfonamide

[1756] Mass spectrum: Found: MH⁺ 476 H.p.l.c. (1) Rt 3.35 min

Example 3725-(3-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1757] Mass spectrum: Found: MH⁺ 487 H.p.l.c. (1) Rt 3.46 min

Example 3735-(2-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1758] Mass spectrum: Found: MH⁺ 496 H.p.l.c. (1) Rt 3.31 min

Example 3745-(2,3-Dichlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1759] Mass spectrum: Found: MH⁺ 530 H.p.l.c. (1) Rt 3.47 min

Example 3755-(2-Fluoro-4-methylphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1760] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.35 min

Example 3765-(6-Amino-5-methylpyridin-3-yl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1761] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 2.13 min

Example 377N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide

[1762] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.26 min

Example 3785-(3-Furyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1763] Mass spectrum: Found: MH⁺ 451 H.p.l.c. (1) Rt 3.35 min

Example 379N-{(3S)-1-[(1S)-1-Methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,3′-bithiophene-5-sulfonamide

[1764] Mass spectrum: Found: MH⁺ 468 H.p.l.c. (1) Rt 3.47 min

Example 3805-(3-Aminophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1765] Mass spectrum: Found: MH⁺ 477 H.p.l.c. (1) Rt 3.01 min

Example 3815-(2-Fluorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1766] Mass spectrum: Found: MH⁺ 480 H.p.l.c. (1) Rt 3.56 min

Example 3825-(2-Hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1767] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.41 min

Example 383 and Example 384N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate [Isomer 1 and Isomer 2]

[1768] To a solution of benzylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinatecompound with formic acid (1:1) (0.060 g) in methanol (4 ml) were addedpotassium carbonate (0.3 g) and water (2 ml) and the mixture left tostir for 5 h. The mixture was concentrated under reduced pressure andthe inorganics removed using SPE (6 g OASIS™ HLB Extraction Cartridge,eluting with water and then methanol) to give a clear gum, which waspurified by mass directed preparative h.p.l.c. to give the titlecompounds (Isomer 1, 0.011 g; Isomer 2, 0.016 g) as white solids.

[1769] Isomer 1 Mass spectrum: Found: MH⁺ 591 H.p.l.c. (1) Rt 2.42 min

[1770] Isomer 2 Mass spectrum: Found: MH⁺ 591 H.p.l.c. (1) Rt 2.46 min

Example 3855-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzofuran-2-sulfonamide

[1771] To a solution of(3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one(0.077 g) in anhydrous acetonitrile (2ml) were added5-chloro-1-benzofuran-2-sulfonyl chloride (0.043 g) in acetonitrile (2ml) and pyridine (0.057 ml), and the mixture was stirred at roomtemperature for 72 h. Saturated ammonium chloride solution (2 ml) wasadded and the resultant mixture stirred at room temperature for 20 min.The mixture was concentrated under reduced pressure and the residuepartitioned between chloroform and hydrochloric acid (2M). The organiclayer was washed with saturated sodium bicarbonate and brine. Theorganic layer was isolated, dried (over magnesium sulphate) andconcentrated under reduced pressure to give the title compound (0.043 g)as a white solid.

[1772] Mass spectrum: Found: MH⁺ 456 H.p.l.c. (1) Rt 2.78 min

Example 386(E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamideRoute 1

[1773] To a solution of(3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one(14.9 g) in anhydrous acetonitrile (750 ml) were added(E)-2-(5-chlorothien-2-yl)ethenesulfonyl chloride (16.5 g) inacetonitrile (250 ml) and pyridine (11 ml), and the mixture was stirredat room temperature for 72 h. Saturated ammonium chloride solution wasadded and the resultant mixture stirred at room temperature for 30 min.The mixture was concentrated under reduced pressure and the residuepartitioned between chloroform and a 1:1 mixture of hydrochloric acid(2M) and water. The organic layer was washed with a 1:1 mixture ofsaturated sodium bicarbonate and water, and brine. The organic layer wasisolated, dried (over magnesium sulphate) and concentrated under reducedpressure to give the title compound (19.3 g) as a white solid.

[1774] Mass spectrum: Found: MH⁺ 448 H.p.l.c. (1) Rt 2.99 min ¹H NMR(CDCl₃):δ 7.48(1H, d), 7.08(1H, d), 6.90(1H, d), 6.55(1H, d), 5.12(1H,br.d), 5.06(1H, q), 3.96(1H, m), 3.70-3.48(9H, m), 3.35(1H, m), 2.62(1H,m), 2.05(1H, m), 1.34(3H, d) ppm.

Route 2

[1775] To a mixture ofN-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide(0.028 g), tris(dibenzylideneacetone)dipalladium (0) (0.0028 g) and2-(di-t-butylphosphino)biphenyl (0.0037 g) under nitrogen, was added drydioxan (0.25 ml) and the mixture was stirred for 5 min at roomtemperature. N,N-Di-isopropylethylamine (0.02 ml) followed by2-bromo-5-chlorothiophene (0.016 ml) in dry dioxan (0.25 ml) were thenadded and the resultant solution was stirred at room temperature for 19h and then heated at 80° C. for 1 h. The reaction was lowered to 60° C.and maintained at this temperature for 20 h. Evaporation of the cooledreaction mixture under a stream of nitrogen gave a residue that waspurified by SPE (silica; using an OPTIX. Gradient elution (flow rate 10ml/min; fraction size 10 ml; UV detector set at λ_(max) 254 nm; 0 to 50%ethyl acetate-cyclohexane over 5 min, followed by 50% to 100% ethylacetate-cyclohexane for 11 min and then 100% ethyl acetate for 4 min])gave the title compound (0.0187 g) as a clear oil.

[1776] Using similar chemistry to that described for Example 386Route 1,the following were prepared:

Example 3875-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1777] Mass spectrum: Found: MH⁺ 472 H.p.l.c. (1) Rt 2.9 min ¹H NMR(CDCl₃):δ 7.87(1H, d), 7.86(1H, m), 7.78(1H, dm), 7.46(1H, dd), 5.58(1H,br.d), 5.02(1 H, q), 3.91(1H, m), 3.69-3.44(9H, m), 3.34(1H, m),2.65(1H, m), 2.10(1H, m), 1.31(3H, d) ppm.

Example 3886-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide

[1778] Mass spectrum: Found: MH⁺ 472 H.p.l.c. (1) Rt 2.96 min ¹H NMR(CDCl₃):δ 7.89(1H, s), 7.85(1H, br.m), 7.81(1H, d), 7.44(1H, dd),5.46(1H, br.d), 5.01(1H, q), 3.90(1H, m), 3.73-3.48(9H, m), 3.34(1H, m),2.67(1H, m), 2.10(1H, m), 1.31(3H, d) ppm.

Example 3895-Chloro-3-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-benzothiophene-2-sulfonamide

[1779] Mass spectrum: Found: MH⁺ 486 H.p.l.c. (1) Rt 3.1 1 min

Example 3903-Cyano-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}benzenesulfonamide

[1780] Mass spectrum: Found: MH⁺ 407 H.p.l.c. (1) Rt 2.4 min

Example 3914-Cyano-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}benzenesulfonamide

[1781] Mass spectrum: Found: MH⁺ 407 H.p.l.c. (1) Rt 2.4 min

Example 3925-(5-Chloro-1,3,4-thiadiazol-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1782] Mass spectrum: Found: MH⁺ 506 H.p.l.c. (1) Rt 2.82 min

[1783] Two additional compounds, Examples 440 and 441 were preparedusing similar chemistry.

Example 3936-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide

[1784] Using Example 388 and 1-bromo-2-butanone, and the syntheticprocedure described for Example 293, the title compound was prepared.

[1785] Mass spectrum: Found: MH⁺ 542 H.p.l.c. (1) Rt 3.28 min

[1786] Using similar chemistry, the following was prepared:

Example 394N2-[(6-Chloro-1-benzothien-2-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1787] Mass spectrum: Found: MH⁺ 529 H.p.l.c. (1) Rt 2.86 min

Example 3955-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide

[1788] Using Example 387 and 1-bromo-2-butanone, and the syntheticprocedure described for Example 293, the title compound was prepared.

[1789] Mass spectrum: Found: MH⁺ 542 H.p.l.c. (1) Rt 3.27 min

[1790] Using similar chemistry, the following was prepared:

Example 396N2-[(5-Chloro-1-benzothien-2-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1791] Mass spectrum: Found: MH⁺ 529 H.p.l.c. (1) Rt 2.85 min

Example 3976-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-phenylnaphthalene-2-sulfonamide

[1792] A mixture of Example 1 (0.0206 g), phenylboronic acid (0.0162mg), copper (II) acetate (0.016 g), triethylamine 0.123 ml) and powered4 Å molecular sieves (dried, 0.1 g) in dry DCM (0.5 ml) was stirred atroom temperature for 6 days. The reaction mixture was filtered using SPE(silica, eluting with 30% methanol in ethyl acetate). The organicfraction was concentrated under reduced pressure to give a brown residuethat was purified by mass directed preparative h.p.l.c. to give thetitle compound (0.0062 g) as a gum.

[1793] Mass spectrum: Found: MH⁺ 542 H.p.l.c. (1) Rt 3.38 min

[1794] Using similar chemistry, the following were prepared:

Example 3986-Chloro-N-(4-fluorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide

[1795] Mass spectrum: Found: MH⁺ 560 H.p.l.c. (1) Rt 3.43 min

Example 3996-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-4-ylnaphthalene-2-sulfonamide

[1796] Mass spectrum: Found: MH⁺ 543

[1797] H.p.l.c. (1) Rt 3.06 min

Example 4006-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-3-ylnaphthalene-2-sulfonamide

[1798] Mass spectrum: Found: MH⁺ 543 H.p.l.c. (1) Rt 3.10 min

Example 4016-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-thien-3-ylnaphthalene-2-sulfonamide

[1799] Mass spectrum: Found: MH⁺ 548 H.p.l.c. (1) Rt 3.38 min

Example 4025-Bromo-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}thiophene-2-sulfonamide

[1800] Intermediate 99 (0.025 g of resin) was treated withtrifluoroacetic acid-DCM (1:1, 1 ml) and shaken for 2 h and filtered.The filtrate was concentrated under a stream of nitrogen to give thetitle compound (0.0025 g) as an off-white glass.

[1801] Mass spectrum: Found: MH⁺ 465 H.p.l.c. (1) Rt 3.09 min

Example 403N-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate and Example 404 Benzyl(3R)-1-((2S)-2-{(3S)-3-[(2-naphthylsulfonyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-ylcarbamate

[1802] A mixture of benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate(0.350 g), 10% palladium on carbon (0.035 g) and ethanol (1000 ml) wasstirred under an atmosphere of hydrogen for 17 h. The reaction mixturewas filtered through Harbolite™ and the filtrate was concentrated underreduced pressure to give an oil. The oil was partially purified usingSPE (silica, eluting with methanol and then 10% aqueous ammonia inmethanol) and then fully purified using mass directed preparativeh.p.l.c. to give the title compounds (Example 403, 0.01 g; Example 404,0.028 g), both as oils.

Example 403

[1803] Mass spectrum: Found: MH⁺ 445 H.p.l.c. (1) Rt 2.37 min

Example 404

[1804] Mass spectrum: Found: MH⁻ 577 H.p.l.c. (1) Rt 3.27 min

Example 405N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate and Example 406 Benzyl(3S)-1-((2S)-2-{(3S)-3-[(2-naphthylsulfonyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-ylcarbamate

[1805] Using benzyl(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamateand the synthetic procedure described for Examples 403 and 404, thetitle compounds were prepared.

Example 405

[1806] Mass spectrum: Found: MH⁺ 445 H.p.l.c. (1) Rt 2.55 min

Example 406

[1807] Mass spectrum: Found: MH⁻ 577 H.p.l.c. (1) Rt 3.37 min

Example 407 tert-Butyl(1R,5S)-7-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

[1808] Using(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid and 3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid,1,1-dimethylethyl ester* and the synthetic procedure described inExample 1, the title compound was prepared.

[1809] Mass spectrum: Found: MH⁺ 605 H.p.l.c. (1) Rt 3.44 min

Example 4086-Chloro-N-((3S)-1{(1S)-2-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1810] A mixture of Example 407 (0.199 g) and trifluoroacetic acid (2ml) in DCM (6 ml) was stirred at room temperature for 2 h and thenconcentrated under reduced pressure to give an oil. Saturated aqueoussodium bicarbonate (10 ml) was added and the resultant mixture extractedwith DCM. The combined organic extracts were dried (over magnesiumsulphate) and concentrated under reduced pressure to give the titlecompound (0.173 g) as a light brown foam.

[1811] Mass spectrum: Found: MH⁺ 505 H.p.l.c. (1) Rt 2.60 min

Example 409N1-[(1R,5S)-7-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-3-(N,N-dimethylglycyl)-3,7-diazabicyclo[3.3.1]non-2-yl]-N1-[(1S,5R)-7-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonamide

[1812] A mixture of N,N-dimethylglycine (0.0062 g), HOBT (0.0088 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.0124 g)and N,N-di-isopropylethylamine (0.0215 ml) in dry DMF (0.05 ml) wassonicated for 2 min. A solution of compound of Example 408 (0.025 g) indry DMF (0.2 ml) was added and the resultant mixture sonicated for afurther 2 min. The mixture was then stirred at room temperature for 18 hand concentrated under reduced pressure to give a gum-like residue,which was purified using mass directed preparative h.p.l.c. to give thetitle compound (0.02 g) as an oil.

[1813] Mass spectrum: Found: MH⁺ 590 H.p.l.c. (1) Rt 2.57 min

Example 4102-{(1R,5S)-7-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-N,N,N-trimethyl-2-oxoethanaminiumchloride

[1814] Using Example 408 and betaine hydrochloride, and the syntheticprocedure described for Example 409, the title compound was prepared.

[1815] Mass spectrum: Found: MH⁺ 604 H.p.l.c. (1) Rt 2.57 min

Example 4116-Chloro-N-((3S)-1-{(1S)-2-[(1R,5S)-3-(N-methylglycyl)-7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide

[1816] Intermediate 99 (0.029 g) was dissolved in DCM (1.5 ml) andtreated with trifluoroacetic acid (0.5 ml). The resultant mixture wasstirred at room temperature for 1.5 h and then concentrated underreduced pressure. The residue was treated with saturated aqueous sodiumbicarbonate (5 ml) and extracted with DCM. The combined organic extractswere dried (over magnesium sulphate), filtered and concentrated underreduced pressure to give the title compound (0.026 g) as a gum.

[1817] Mass spectrum: Found: MH⁺ 576 H.p.l.c. (1) Rt 2.61 min

Example 412N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamideformate

[1818] A mixture of Example 407 (0.0124 g), potassium carbonate (0.009g) and 2-bromoacetamide (0.0029 g) in dry DMF (0.21 ml) was stirred atroom temperature for 19 h, and then additional 2-bromoacetamide (0.0015g) was added. After stirring for a further 5 h, the mixture was quenchedwith water (2 ml), extracted with ethyl acetate, dried (over magnesiumsulphate) and filtered. The combined organic extracts were concentratedunder reduced pressure to give an oil which was treated withtrifluoroacetic acid-DCM (2 ml; 1:1), and stirred at room temperaturefor 5 h. The mixture was concentrated under reduced pressure and theresidue purified using mass directed preparative h.p.l.c. to give thetitle compound (0.004 g) as an oil.

[1819] Mass spectrum: Found: MH⁺ 562 H.p.l.c. (1) Rt 2.45 min

Example 4136-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{(1R,5S)-7-[2-(methylamino)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1820] A mixture of Example 408 (0.0198 g),N-(2-chloroethyl)-N-methylamine hydrochloride (0.076 g) and sodiumbicarbonate (0.1 g) in ethanol (0.45 ml) was heated at 80° C. for 20 h.The cooled reaction mixture was diluted with brine, extracted with DCM,dried (over magnesium sulphate) and concentrated under reduced pressure.The resultant residue was purified using mass directed preparativeh.p.l.c. to give the title compound (0.008 g) as a clear gum.

[1821] Mass spectrum: Found: MH⁺ 562 H.p.l.c. (1) Rt 2.29 min

Example 4146-Chloro-N-[2-(dimethylamino)ethyl]-N-[(3S)-1-((1S)-2-{(1R,5S)-7-[2-(dimethylamino)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide

[1822] Using Example 408 and N,N-dimethylaminoethyl chloridehydrochloride, and the synthetic procedure described for Example 413,the title compound was prepared.

[1823] Mass spectrum: Found: MH⁺ 647 H.p.l.c. (1) Rt 2.33 min

Example 4156-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1R,5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamidetrifluoroacetate

[1824] A mixture of 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylicacid, 1,1-dimethylethyl ester* (0.0178g),(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid (0.037 g), HOBT (0.0136 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.0194 g)and N,N-di-isopropylethylamine (0.041 ml) in dry DMF (0.3 ml) wasstirred at room temperature for 5 days and then concentrated underreduced pressure. The resultant residue was diluted with aqueous sodiumhydroxide (0.5M, 5 ml) and extracted with ethyl acetate. The combinedorganic extracts were concentrated under reduced pressure and theresidue purified using preparative thin layer chromatography (20 cm×20cm 1 mm thick Whatman PKF₂₅₆ SiO₂ plate, eluting with ethyl acetate).The resultant material (0.0012 g) was treated with 10% trifluoroaceticadd-DCM (10 ml) at room temperature for 3 h and concentrated underreduced pressure to give the title compound (0.0011 g) as an oil.

[1825] Mass spectrum: Found: MH⁺ 507 H.p.l.c. (1) Rt 2.52 min

Example 416N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperazin-1-ylethyl]-2-oxopyrrolidin-3-yl}qlycinamidetrifluoroacetate

[1826] Using(2S)-2-((3S)-3-{(2-amino-2-oxoethyl)[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoicacid and 1-Boc-piperazine, and the synthetic procedure described forExample 1, provided the Intermediate t-butyl ester. This wassubsequently deprotected using trifluoroacetic acid to provide the titlecompound.

[1827] Mass spectrum: Found: MH⁺ 522 H.p.l.c. (1) Rt 2.39 min

Example 417N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamideformate

[1828] Using Intermediate 49 and the procedure described for Example 1,the title compound was prepared.

[1829] Mass spectrum: Found: MH⁺ 550 H.p.l.c. (1) Rt 2.45 min Usingsimilar chemistry, the following were prepared:

Example 418N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide

[1830] Mass spectrum: Found: MH⁺ 551 H.p.l.c. (1) Rt 3.02 min

Example 419N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide

[1831] Mass spectrum: Found: MH⁺ 535 H.p.l.c. (1) Rt 2.83 min

Example 420 and Example 421N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide[Isomer 1 and Isomer 2]

[1832] Isomer 1 Mass spectrum: Found: MH⁺ 585 H.p.l.c. (1) Rt 2.61 min

[1833] Isomer 2 Mass spectrum: Found: MH⁺ 585 H.p.l.c. (1) Rt 2.62 min

Example 422N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide

[1834] Mass spectrum: Found: MH⁺ 564 H.p.l.c. (1) Rt 2.70 min

Example 423 and Example 424N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide[Isomer 1 and Isomer 2]

[1835] Isomer 1 Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 2.70 min

[1836] Isomer 2 Mass spectrum: Found: MH⁺ 584 H.p.l.c. (1) Rt 2.73 min

Example 425N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[2-(4-methylpyridin-2-yl)pyrrolidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide

[1837] Mass spectrum: Found: MH⁺ 599 H.p.l.c. (1) Rt 2.8 min

Example 426(E)-2-(3-Chloro-4-hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1838] Sulphuryl chloride (0.036 ml) was added dropwise to DMF (0.04 ml)at 0° C. and the mixture was stirred at room temperature for 2 h.Intermediate 105 (0.102 g) in cyclohexane (0.2 ml) was added in oneportion and the resultant mixture was heated at 90° C. for 6 h. Thecooled reaction mixture was poured onto ice and extracted with DCM. Thecombined organic extracts were dried (over magnesium sulphate) andconcentrated under reduced pressure to give a brown oil which wastreated with sulphuryl chloride (0.035 ml) and triphenyl phosphine(0.103 g) in dry DCM (ca. 0.5 ml). After stirring for 3 h at roomtemperature, the mixture was filtered through a SPE silica cartridgepreconditioned with cyclohexane. Elution with ethyl acetate gave, afterconcentration under reduced pressure, an orange-brown solid which wasstirred with Intermediate 87 (0.04 g), 4-dimethylaminopyridine (0.021g), di-isopropylethylamine (0.059 ml) in dry DCM (1 ml). After stirringfor 3 days at room temperature under nitrogen, the mixture wasconcentrated under reduced pressure. The residue was purified initiallyusing SPE (silica) followed by mass directed preparative h.p.l.c. togive the title compound (0.0035 g) as a white solid.

[1839] Mass spectrum: Found: MH⁺ 458 H.p.l.c. (1) Rt 2.58 min

Example 427(E)-2-(4-Chloro-3-hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1840] To a solution of(E)-2-(3-{[tert-butyl(diphenyl)silyl]oxy}-4-chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide(0.0078 g) in THF (0.3 ml) at −78° C. under nitrogen, tetran-butylammonium fluoride (1M in THF, 0.014 ml) was added. The mixturewas allowed to warm to room tempertaure over 3 days and thenconcentrated under reduced pressure. The residue was purified using massdirected preparative h.p.l.c. to give the title compound (0.0043 g) as aclear film.

[1841] Mass spectrum: Found: MH⁺ 458 H.p.l.c. (1) Rt 2.67 min

Example 4286-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulfonamideformate

[1842] Example 1 (0.05 g) was dissolved in DMF (1 ml) and treated withchloroethylmorpholine hydrochloride (0.062 g) and potassium carbonate(0.093 g), and stirred at 40° C. for 2 h. The mixture was then heated at80° C. for 8 h, cooled and treated with ethyl acetate and water. Theorganic extraxt was dried (over magnesium sulphate) and concentratedunder reduced pressure. The residue was purified using mass directedpreparative h.p.l.c. to give the title compound (0.018 g) as a whitesolid.

[1843] Mass spectrum: Found: MH⁺ 579 H.p.l.c. (1) Rt 2.56 min

[1844] Using similar chemistry, the following were prepared:

Example 4296-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-pyrrolidin-1-ylethyl)naphthalene-2-sulfonamideformate

[1845] Mass spectrum: Found: MH⁺ 563 H.p.l.c. (1) Rt 2.58 min

Example 4306-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate

[1846] Mass spectrum: Found: MH⁺ 537 H.p.l.c. (1) Rt 2.53 min

Example 431N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyl]acetamide

[1847] Mass spectrum: Found: MH⁺ 551 H.p.l.c. (1) Rt 2.91 min

Example 4326-Chloro-N-{2-oxo-1-[1-(piperidin-1-ylcarbonyl)propyl]pyrrolidin-3-yl}naphthalene-2-sulfonamide[Isomer 1 and Isomer 2]

[1848] Using2-(3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)butanoicacid [Isomer 1 and Isomer 2] and the synthetic procedure described forExample 1, the title compound was prepared.

[1849] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.37 min

[1850] Using similar chemistry, the following was prepared:

Example 4336-Chloro-N-{2-oxo-1-1-(pyrrolidin-1-ylcarbonyl)propyl]pyrrolidin-3-yl}naphthalene-2-sulfonamide[Isomer 1 and Isomer 2]

[1851] Mass spectrum: Found: MH⁺ 464 H.p.l.c. (1) Rt 3.21 min

Example 4346-Chloro-N-[1-(1-{[(2S)-2-methylpiperidin-1-yl]carbonyl}propyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide[Isomer 3 and Isomer 4]

[1852] Using2-(3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)butanoicacid [Isomer 3 and Isomer 4] and the synthetic procedure described forExample 1, the title compound was prepared.

[1853] Mass spectrum: Found: MH⁺ 492 H.p.l.c. (1) Rt 3.13 min

[1854] Using similar chemistry, the following was prepared:

Example 4356-Chloro-N-{2-oxo-1-[1-(piperidin-1-ylcarbonyl)propyl]pyrrolidin-3-yl}naphthalene-2-sulfonamide[Isomer 3 and Isomer 4]

[1855] Mass spectrum: Found: MH⁺ 478 H.p.l.c. (1) Rt 3.12 min

Example 4366-Chloro-N-((3R)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate

[1856] Using Intermediate 31 and the procedure described for Example 1,the title compound was prepared.

[1857] Mass spectrum: Found: MH⁺ 533 H.p.l.c. (1) Rt 2.63 min

Example 4375-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1H-indole-2-sulfonamide

[1858] Intermediate 64 (0.011 g) was dissolved in 1:1 TFA/DCM (0.5 ml)and allowed to stand at room temperature for 1 h. The mixture wasconcentrated under reduced pressure and the residue solvents partitionedbetween saturated aqueous sodium bicarbonate and DCM. The separatedorganic phase was dried (over magnesium sulphate) and concentrated undera stream of nitrogen to give the title compound (0.0082 g) as whitesolid.

[1859] Mass spectrum: Found: MH⁺ 455 H.p.l.c. (1) Rt 2.97 min

Example 4386-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1,3-benzothiazole-2-sulfonamide

[1860] Intermediate 66 (0.1 g) was stirred at room temperature inanhydrous acetone (3 ml) and 5% aqueous potassium permanganate (1.35 ml)for 3 h, after which additional acetone (3 ml) and 5% aqueous potassiumpermanganate (1.35 ml) were added. The reaction mixture was stirred fora further 18 h and filtered through Celite™. The filtrate wasconcentrated under reduced pressure and the residue purified by massdirected preparative h.p.l.c to give the title compound (0.0062 g) as awhite solid.

[1861] Mass spectrum: Found: MH⁺ 473 H.p.l.c. (1) Rt 2.98 min

Example 4391-(3-Cyanophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}methanesulfonamide

[1862] The title compound was prepared using Intermediate 23 and(3-cyanophenyl)methanesulfonyl chloride, and the synthetic proceduredescribed for Example 386 (Route 1).

[1863] Mass spectrum: Found: MH⁺ 419 H.p.l.c. (1) Rt min

Example 4405-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}thieno[2,3-b]pyridine-2-sulfonamide

[1864] The title compound was prepared using Intermediates 57 and 87,and the synthetic procedure described for Example 386 (Route 1). Massspectrum: Found: MH⁺ 473 H.p.l.c. (1) Rt 2.64 min

Example 4415-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}thieno[3.2-b]pyridine-2-sulfonamide

[1865] The title compound was prepared using Intermediates 87 and 118,and the synthetic procedure described for Example 386 (Route 1).

[1866] Mass spectrum: Found: MH⁺ 473 H.p.l.c. (1) Rt 2.53 min

Example 4426-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]-2-oxopyrrolidinyl}thieno[3,2-b]pyridine-2-sulfonamide

[1867] The title compound was similarly prepared using Intermediate 87and 6-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride*, and thesynthetic procedure decribed for Example 386 (Route 1).

[1868] Mass spectrum: Found: MH⁺ 473 H.p.l.c. (I) Rt 2.61 min

Example 443(E)-2-(5-Chlorothien-2-yl)-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide

[1869] Sodium hydride (60% dispersion in oil, 0.011 g) was added totrimethysulphonium iodide (0.059 g) in dimethylsulphoxide (2 ml) between5-10° C., and the resultant mixture was stirred at room temperature for30 min. Example 386 (0.1 g) in dry THF (2 ml) was added between 5-10°C., and the solution stirred at room temperature for 2.25 h, at 50° C.for 70 h, cooled to room temperature and poured onto ice/water. Theaqueous mixture was extracted with ethyl acetate and the combined, dried(over magnesium sulphate) organic extracts were concentrated underreduced pressure. The residue was purified using mass directedpreparative h.p.l.c. to give the title compound (0.038 g) as acolourless oil.

[1870] Mass spectrum: Found: MH⁺ 462 H.p.l.c. (1) Rt 2.82 min

In vitro Assay for Inhibition of Factor Xa

[1871] Compounds of the present invention were tested for their FactorXa inhibitory activity as determined in vitro by their ability toinhibit human Factor Xa in a chromogenic assay, usingN-α-benzyloxycarbonyl-D-Arg-Gly-Arg-p-nitroanilide as the chromogenicsubstrate. Compounds were diluted from a 10 mM stock solution indimethylsulfoxide at appropriate concentrations. Assay was performed atroom temperature using buffer consisting of: 50 mM Tris-HCl, 150 mMNaCl, 5 mM CaCl2, pH 7.4. containing human Factor Xa (final conc. Of0.0015 U.ml-1). Compound and enzyme were preincubated for 15 min priorto addition of the substrate (final conc. of 200 μM). The reaction wasstopped after 30 min with the addition of soybean trypsin inhibitor orH-D-PHE-PRO-ARG-Chloromethylketone. BioTek EL340 or Tecan SpectraFluorPlus plate readers were used to monitor the absorbance at 405 nM. Toobtain IC50 values the data were analysed using ActivityBase® andXLfit®.

[1872] All of the synthetic Example compounds tested exhibitedmeasurable FXa inhibitory activity. Preferably compounds have an IC₅₀value of less than 2 μM, more preferably compounds have an IC₅₀ value ofless than 0.1 μM.

Measurement of Prothrombin Time (PT)—Test 1

[1873] Blood was collected into a sodium citrate solution (ratio 9:1) togive a final concentration of 0.38% citrate. Plasma was generated bycentrifugation of citrated blood samples at 1200×g for 20 min at 4° C.

[1874] The PT test was performed at 37° C. in plastic cuvettescontaining a magnetic ball bearing. 50 μL of citrated plasma and either25 μL of 2.8% DMSO for control or 25 μL of test compound (dissolved inDMSO and diluted in water and 2.8% DMSO to give 0.4% DMSO final inassay) at a concentration of 7-times the final desired concentration waspippetted into each cuvette. This mixture was incubated for 1 min at 37°C. before adding 100 μL of thromboplastin mixture (comprisinglyophilised rabbit thromboplastin and calcium chloride which wasreconstituted in distilled water as per manufacturer's [Sigma]instructions). On addition of the thromboplastin mixture, the timer wasautomatically started and continued until the plasma clotted. The timeto clotting was recorded (normal range for human plasma is 10-13seconds).

Method for Measurement of Prothrombin Time (PT)—Test 2

[1875] Blood is collected into a sodium citrate solution (ratio 9:1) togive a final concentration of 0.38% citrate. Plasma is generated bycentrifugation of citrated blood samples at 1200×g for 20 min at 4° C.

[1876] The PT test is performed at 37° C. in plastic cassettes and usinga MCA210 Microsample Coagulation Analyzer (Bio/Data Corporation). Forassay, 25 ul of plasma containing test compound at concentrationsranging from 0.1 to 100 uM (made from a 1 mM stock solution in 10% DMSOand plasma) and 25 ul of Thromboplastin C Plus (Dade Berhing) areautomatically injected into the cassette. Upon addition of theThromboplastin C Plus, the instrument determines and records the time toclot (normal range for human plasma is 10-13 seconds).

General Purification and Analytical Methods

[1877] Analytical HPLC was conducted on a Supelcosil LCABZ+PLUS column(3 μm, 3.3 cm×4.6 mm ID) eluting with 0.1% HCO₂H and 0.01 M ammoniumacetate in water (solvent A), and 95% acetonitrile and 0.05% HCO₂H inwater (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0→100% B, 4.2-5.3 minutes 100% B, 5.3-5.5 minutes100→0% B at a flow rate of 3 ml/minutes (System 1). The mass spectra(MS) were recorded on a Fisons VG Platform mass spectrometer usingelectrospray positive ionisation [(ES+ve to give MH⁺ and M(NH₄)⁺molecular ions] or electrospray negative ionisation [(ES-ve to give(M-H)⁻ molecular ion] modes.

[1878]¹H nmr spectra were recorded using a Bruker DPX 400 MHzspectrometer using tetramethylsilane as the external standard.

[1879] Biotage™ chromatography refers to purification carried out usingequipment sold by Dyax Corporation (either the Flash 40i or Flash 150i)and cartridges pre-packed with KPSil.

[1880] Mass directed autoprep refers to methods where the material waspurified by high performance liquid chromatography on a HPLCABZ+5 μmcolumn (5 cm×10 mm i.d.) with 0.1% HCO₂H in water and 95% MeCN, 5% water(0.5% HCO₂H) utilising the following gradient elution conditions: 0-1.0minutes 5% B, 1.0-8.0 minutes 5→30% B, 8.0-8.9 minutes 30% B, 8.9-9.0minutes 30→95% B, 9.0-9.9 minutes 95% B, 9.9-10 minutes 95→0% B at a lowrate of 8 ml minutes⁻¹ (System 2). The Gilson 202-fracton collector wastriggered by a VG Plafform Mass Spectrometer on detecting the mass ofinterest.

[1881] Hydrpophobic frits refers to filtration tubes sold by Whatman.

[1882] SPE (solid phase extraction) refers to the use of cartridges soldby International Sorbent Technology Ltd.

[1883] TLC (thin layer chromatography) refers to the use of TLC platessold by Merck coated with silica gel 60 F₂₅₄.

LC/MS System (3)

[1884] Method 2 was conducted on a Waters Xtera RP18 column (3 μm, 15cm×2.1 mm ID) eluting with solvent A (0.1% HCO2H and water) and solventB (100% acetonitrile, 0.1% HCO2H and reserpine 2.5 μgml-1) at 20° C. Thefollowing elution gradient was ran: 0-2.0 minutes 0% B; 2.0-18.0 minutes0-100% B; 18.0-20.0 minutes 100% B; 20.0-22.0 minutes 100-0% B;22.0-30.0 minutes 0% B, at a flow rate of 0.4 ml/minutes. The massspectra (MS) were recorded on a Micromass QTOF 2 spectrometer usingelectrospray positive ionisation [ES+ve to give MH+].

[1885] Note: The number given in brackets in the Examples andIntermediates above, e.g. H.p.l.c. (1), specifies the LC/MS method used.

1. A compound of formula (Ic):

wherein: R¹ represents hydrogen, —C₁₋₆alkyl, —C₃₋₆alkenyl, —C₃₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c),—C₂₋₃alkyl OCONR^(b)R^(c), —C₂₋₃alkylOC₁₋₆alkyl, —C₂₋₃alkylOCH₂phenyl,phenyl or 5- or 6-membered aromatic heterocyclic group containing atleast one heteroatom selected from O, N or S, the phenyl or aromaticheterocyclic group being optionally substituted by one or moresubstitutents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH, or R¹ represents a group X—W; Xrepresents —C₁₋₃alkylene-, propenylene, propynylene; W represents —CN,—CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl, —CO₂C₃₋₆alkenyl,phenyl or 5- or 6-membered aromatic or non-aromatic heterocyclic groupcontaining at least one heteroatom selected from O, N or S, the phenylor aromatic or non-aromatic heterocyclic group being optionallysubstituted by one or more substitutents selected from: —C₁₋₃alkyl,—C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; R⁸represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or 6-memberedheterocyclic group containing at least one heteroatom selected from O, Nor S, the phenyl or heterocyclic group being optionally substituted byone or more substituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy,—C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; R^(b) and R^(c)independently represent hydrogen or —C₁₋₄alkyl; R² and R³ independentlyrepresent hydrogen, —C₁₋₃alkyl or —CF₃, with the proviso that one of R²and R³ is —C₁₋₃alkyl or —CF₃ and the other is hydrogen; R⁴ and R⁵,together with the N atom to which they are bonded, form a 4-, 5-, 6-, 7-or 8-membered non-aromatic heterocyclic ring, bridged or unbridged,optionally containing an additional heteroatom selected from O, N or S,and optionally substituted by: (i) one or more substitutents selectedfrom: —NH₂, —CF₃, F, —OH, ═O, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy,—C₁₋₆alkylOH, —(C₁₋₃alkyl)NR^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c),—NHSO₂CF₃, —NHSO₂(C₀₋₃alkyl)R^(a), —NHCH₂COCH₂O(C₁₋₃alkyl),—(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —CONHC₂₋₃alkylOH, —CH₂NHC₂₋₃alkylOH,—CH₂OC₁₋₃alkyl, —COCH₂NR^(b)R^(c), —COCH₂N⁺(CH₃)₃ and —CH₂SO₂C₁₋₃alkyl;(ii) a group —NHCOR^(d) or —NR^(b)R^(d), R^(d) represents —C₁₋₆alkyl,—C₂₋₆alkynyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —C₁₋₃alkylCO₂H,—C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylCONR^(b)R^(c)and —C₁₋₃alkylOC₁₋₃alkyl; (iii) a group —Y—R⁶, Y represents—C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-, —NHC₁₋₃alkylene-, —CO—,—C₁₋₃alklNH—, —C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂— or adirect link, R^(e) represents phenyl, phenyl, a 5- or 6-memberedheterocycle containing at least one heteroatom selected from O, N or S,or a 5- or 6-membered cycloalkyl, each of which is optionallysubstituted by one or more substituents selected from: —C₁₋₃alkyl,—C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; or(iv) a second ring R^(f) which is fused to the non-aromatic heterocyclicring formed by R⁴ and R⁵, wherein R^(f) represents phenyl, a 5- or6-membered cycloalkyl group or a 5- or 6-membered aromatic heterocyclicgroup containing at least one heteroatom selected from O, N or S, andthe fused bicyclic group is optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; with the proviso that where thesubstituent on the non-aromatic ring formed by R⁴ and R⁵ is —NH₂, —OH,—C₁₋₆alkoxy, —NHSO₂CF₃, —NHSO₂(C₀₋₃alkyl)R^(a), —NHCOR^(d),—NR^(b)R^(d), —NHCOR^(e), —NR^(b)R^(d), —NHCOR^(e),—NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e),—NHCH₂COCH₂O(C₁₋₃alkyl), the substituent is not attached to a ringcarbon atom adjacent to a heteroatom; R⁶ represents: (i) a fusedbicyclic group —R⁹R^(h); (ii) a group —R^(g)—R^(h); (iii) a group—Z—R^(h) wherein Z represents —C₁₋₃alkylene-, —C₂₋₃alkenylene- or adirect link; wherein R⁹ and R^(h) independently represent phenyl or a 5-or 6-membered aromatic heterocyclic group containing at least oneheteroatom selected from O, N or S, the phenyl or aromatic heterocyclicgroup being optionally substituted by one or more substituents selectedfrom: —C₁₋₃alkyl, —C₁₋₃alkoxy, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH;and pharmaceutically acceptable derivatives thereof.
 2. A compound offormula (I)

wherein: R¹ represents hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₂₋₃alkylOH, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),—C₂₋₃alkylNHCO₂R^(b), —C₂₋₃alkylNHSO₂R^(b), —C₂₋₃alkylNHCONR^(b)R^(c) ora group X—W; X represents —C₁₋₃alkylene-, propenylene, propynylene; Wrepresents —CN, —CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl,—CO₂C₂₋₆alkenyl, —OCONR^(b)R^(c), —OC₁₋₆alkyl, —OCH₂phenyl, phenyl or 5-or 6-membered aromatic heterocyclic group containing at least oneheteroatom selected from O, N or S, the phenyl or aromatic heterocyclicgroup being optionally substituted by one or more substitutents selectedfrom: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂,—CO₂H and —OH; R^(a) represents hydrogen, —C₁₋₃alkyl, phenyl or a 5- or6-membered heterocyclic group containing at least one heteroatomselected from O, N or S, the phenyl or heterocyclic group beingoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH; R^(b) and R^(c) independently represent hydrogen or —C₁₋₃alkyl;R² and R³ independently represent hydrogen, —C₁₋₃alkyl or —CF₃, with theproviso that when one of R² and R³ is —C₁₋₃alkyl or —CF₃, the other ishydrogen; R⁴ and R⁵, together with the N atom to which they are bonded,form a 5, 6- or 7-membered non-aromatic heterocyclic ring, bridged orunbridged, optionally containing an additional heteroatom selected fromO, N or S, and optionally substituted by: (i) one or more substitutentsselected from: —NH₂, —CF₃, F, —OH, ═O, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy,—C₁₋₆alkylOH —(C₁₋₃alkyl)NR^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c),—NHSO₂CF₃, —NHSO₂(C₀₋₃alkyl)R^(a) and (C₀₋₃alkyl)CO₂C₁₋₃alkyl; (ii) agroup —NHCOR^(d) or —NR^(b)R^(d), R^(d) represents —C₁₋₆alkyl,—C₂₋₆alkynyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH, —C₁₋₃alkylCO₂H,—C₁₋₃alkylNR^(b)R^(c), —C₁₋₃alkylCO₂C₁₋₃alkyl or—C₁₋₃alkylCONR^(b)R^(c); (iii) a group —Y—R^(e), Y represents—C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-, —NHC₁₋₃alkylene-, —CO—,—C₁₋₃alkylNH—, —C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂—, —CH₂NHSO₂CH₂— or adirect link, R^(e) represents phenyl, a 5 or 6-membered cycloalkyl or a5- or 6-membered heterocycle containing at least one heteroatom selectedfrom O, N or S, each of which is optionally substituted by one or moresubstituents selected from: —C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH,halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH or (iv) a second ring R^(f)which is fused to the non-aromatic heterocyclic ring formed by R⁴ andR⁵, wherein R^(f) represents phenyl, a 5- or 6-membered cycloalkyl groupor a 5- or 6-membered aromatic heterocyclic group containing at leastone heteroatom selected from O, N or S, and the fused bicyclic group isoptionally substituted by one or more substituents selected from:—C₁₋₃alkyl, —C₁₋₃alkoxy, —C₁₋₃alkylOH, halogen, —CN, —CF₃, —NH₂, —CO₂Hand —OH; with the proviso that where the substituent on the non-aromaticring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy, —NHSO₂CF₃,—NHSO₂(C₀₋₃alkyl)R^(a), —NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e),—NHCO₂C₁₋₃alkyleneR^(e) or —NHC₁₋₃alkyleneR^(e), the substituent is notattached to a ring carbon atom adjacent to a heteroatom; R⁶ represents:(i) a fused bicyclic group —R^(g)R^(h); (ii) a group —R^(g)—R^(h); (iii)a group —Z—R^(h) wherein Z represents —C₁₋₃alkylene-, —C₂₋₃alkenylene-or a direct link; wherein R^(g) and R^(h) independently represent phenylor a 5- or 6-membered aromatic heterocyclic group containing at leastone heteroatom selected from O, N or S, each of which is optionallysubstituted by one or more substituents selected from: —C₁₋₃alkyl,—C₁₋₃alkoxy, halogen, —CN, —CF₃, —NH₂, —CO₂H and —OH; andpharmaceutically acceptable salts or solvates thereof.
 3. A compound asclaimed in claim 1 or claim 2 wherein R¹ represents hydrogen,—C₁₋₆alkyl, —C₂₋₆alkenyl or a group X—W wherein X represents—C₁₋₃alkylene- and W represents —CN, —CO₂H, —CONR^(b)R^(c),—COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-membered aromatic heterocyclicgroup containing at least one heteroatom selected from O, N or S.
 4. Acompound as claimed in claim 1 wherein R¹ represents hydrogen,—C₁₋₆alkyl, —C₃₋₆alkenyl, —C₂₋₃alkylNR^(b)R^(a), —C₂₋₃alkylNHCOR^(a),phenyl or a 5- or 6-membered aromatic heterocycle, or R¹ represents agroup X—W wherein X represents —C₁₋₆alkylene- and W represents —CN,—CO₂H, —CONR^(b)R^(c), —COC₁₋₆alkyl, —CO₂C₁₋₆alkyl or a 5- or 6-memberedaromatic or non-aromatic heterocyclic group containing at least oneheteroatom selected from O, N or S.
 5. A compound as claimed in any oneor claims 1-4 wherein R² represents —C₁₋₃alkyl or hydrogen.
 6. Acompound as claimed in any one of claims 1-5 wherein R³ represents—C₁₋₃alkyl or hydrogen.
 7. A compound as claimed in any one of claims1-6 wherein R⁴ and R⁵, together with the N atom to which they arebonded, form a 5- or 6-membered non-aromatic heterocyclic ring,optionally containing an additional heteroatom selected from O, N or S,and optionally substituted by: (i) one or more subsituents selectedfrom: —NH₂, —CF₃, —OH, —CO₂H, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH,—(C₁₋₃alkyl)NR^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c) and —NHSO₂CF₃; (ii) agroup NHCOR^(d) wherein R^(d) represents —C_(alkyl), —C₂₋₆alkynyl,—C₁₋₆alkoxy, —C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c),—C₁₋₃alkylCO₂C₁₋₃alkyl or —C₁₋₃alkylCONR^(b)R^(c) or a group NHR^(d)wherein R^(d) represents —C₁₋₆alkyl or —C₁₋₆alkylOH; (iii) a group—Y—R^(e), Y represents —C₁₋₃alkylene-, —NHCO—, —NHCO₂C₁₋₃alkylene-,—NHC₁₋₃alkylene- or —C₁₋₃alkylNHSO₂, R^(e) represents imidazole,pyrrole, pyrazole, pyridine, pyrimidine, furan, oxazole, 1,2,4-triazole,phenyl or pyrrolidine optionally substituted by —C₁₋₃alkyl, NH₂ or—C₁₋₃alkylOH; (iv) a second ring R^(f) which is fused to thenon-aromatic heterocyclic ring formed by R⁴ and R⁵, wherein R^(f)represents cyclohexyl; with the proviso that where the substituent onthe non-aromatic ring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy,—NHSO₂CF₃, —NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e), —NHCO₂C₁₋₃alkyleneR^(e)or —NHC₁₋₃alkyleneR^(e), the substituent is not attached to a ringcarbon atom adjacent to a heteroatom;
 8. A compound as claimed in claim1 wherein R⁴ and R⁵, together with the N atom to which they are bonded,form a 4-, 5-, 6-, 7- or 8-membered non-aromatic heterocyclic ring,selected from: piperidine; pyrrolidine; hexamethyleneimine(homopiperidine); morpholine; thiomorpholine; diazepine;tetrahydro-1,6-naphthyridine; 2-azabicyclo[2.2.1]heptane;2-oxa-5-azabicyclo[2.2.1]heptane; 3,7-diazabicyclo[3.3.1]nonane;9-oxa-3,7-diazabicyclo[3.3.1]nonane; 2-azabicyclo[2.2.2]octane;4,6,7,8-tetrahydro-5h-thieno[3,2-c]azepine; 1,2,5,6-tetrahydropyridine;azetidine; 2,5-dihydro-1h-pyrrole; piperazine; hexahydropyrimidine;tetrahydroquinoline; decahydroquinoline; tetrahydroquinoxaline;dihydroisoindole; tetrahydroisoquinoline;tetrahydro-5h-imidazo[4,5-c]pyridine;1,3,4,5-tetrahydro-2h-2-benzazepine; 2,5-diazabicyclo[2.2.1]heptane;optionally substituted by: (i) one or more substitutents selected from:—NH₂, —CF₃, F, —OH, ═O, —C₁₋₆alkyl, —C₁₋₆alkoxy, —C₁₋₆alkylOH,—(C₁₋₃alkyl)NR^(b)R^(c), —(C₀₋₃alkyl)CONR^(b)R^(c), —NHSO₂CF₃,—NHCH₂COCH₂O(C₁₋₃alkyl), —(C₀₋₃alkyl)CO₂C₁₋₄alkyl, —CONHC₂₋₃alkylOH,—COCH₂NR^(b)R^(c), —COCH₂N⁺(CH₃)₃, —CH₂OC₁₋₃alkyl and —CH₂SO₂C₁₋₃alkyl;(ii) a group —NHCOR^(d) or —NR^(b)R^(d), R^(d) represents —C₁₋₆alkyl,—C₂₋₆alkynyl, —C₁₋₆alkylOH, —C₁₋₃alkylCO₂H, —C₁₋₃alkylNR^(b)R^(c),—C₁₋₃alkylCO₂C₁₋₃alkyl, —C₁₋₃alkylOC₁₋₃alkyl and—C₁₋₃alkylCONR^(b)R^(c); (iii) a group —Y—R^(e), Y represents—C₁₋₃alkylene-, —NHCO—, —NHC₁₋₃alkylene-, —NHCO₂C₁₋₃alkylene-,—C₁₋₃alkylNHCO—, —C₁₋₃alkylNHSO₂—, —CO— or a direct link. R^(e)represents phenyl, pyridine, pyrrole, isoxazole, pyrazole, pyrrolidine,cyclopentyl, triazole, pyrazine, furan, thiazole, imidazole, morpholine,piperazine, pyrimidine, piperidine, each of which is optionallysubstituted by one or more substituents selected from: —C₁₋₃alkyl,halogen, —NH₂; with the proviso that where the substituent on thenon-aromatic ring formed by R⁴ and R⁵ is —NH₂, —OH, —C₁₋₆alkoxy,—NHSO₂CF₃, —NHCOR^(d), —NR^(b)R^(d), —NHCOR^(e), or—NHC₁₋₃alkyleneR^(e), —NHCO₂C₁₋₃alkyleneR^(e), —NHCH₂COCH₂O(C₁₋₃alkyl),the substituent is not attached to a ring carbon atom adjacent to aheteroatom.
 9. A compound as claimed in any one of claims 1-8 wherein R⁶represents


10. A compound as claimed in claim 1 selected from:6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-](1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-2-(4,4-difluoropiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-2-(3,4-difluoropiperidin-1,6-naphthyridin-1(2H)-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-((3S)-1-{(1S)-2-[(1R,4S)-2-Azabicyclo[2.2.1]hept-2-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;N-{1-[(1S)-2-Azepan-1-yl-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;N-{(3S)-1-[(1S)-2-(2-Azabicyclo[2.2.2]oct-2-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;(E)-2-(4-Chlorophenyl)-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)ethenesulfonamideformate;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;5-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;(E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide;MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;N-{[(E)-2-(4Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-thiomorpholin-4-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;N1-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N2,N2-dimethylglycinamide;Methyl3-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;N-{-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;N-{1-[(2S)-2-((3S)-3-{[-(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;6-Chloro-N-ethyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2sulfonamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(5-oxo1,4-diazepan-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamideformate;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamideformate;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamideformate;N-[(5′-Chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino)]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;6-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;tert-ButylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;N-Allyl-6-chloro-N-{1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate;N-[(6-Chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycine;6-Chloro-N-methyl-N-{(3R)-1-[(1R)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-[(6-Chloro-2-naphthyl)sulfonyl]-N-(1-{1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycineformate;(E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide;N2-[(6-Chloro-1-benzothien-2-yl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;6-Chloro-N-((3S)-1-{(1S)-2-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{(1R,5S)-7-[2-(methylamino)ethyl]-3,7-diazabicyclo[3.3.1]non-3-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(1R,5S)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamidetrifluoroacetate;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamideformate;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-1-methyl-2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-4-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-(4-methyl-5-oxo-1,4-diazepan-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-(2-pyridin-3-ylpyrrolidin-1-yl)ethyl]-2-oxopyrrolidin-3-yl}glycinamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulfonamideformate;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-pyrrolidin-1-ylethyl)naphthalene-2-sulfonamideformate;6-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamideformate;N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyl]acetamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamideformate;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;5′-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2′-bithiophene-5-sulfonamide;N-{(3S)-1-[(1S)-2-(3-Aminopiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-6-chloronaphthalene-2-sulfonamide;(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;MethylN-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;(E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-((3S)-1-{(1S)-2-[3-(hydroxymethyl)piperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}acetamide;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[3-(1H-pyrrol-1-ylmethyl)piperidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-2-(3,3-dimethylpiperidin-1-yl)-1-methyl-2-oxoethyl]-2-oxopyrrolidin-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}prop-2-ynamide;N-{1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}1-methyl-1H-pyrrole-3-carboxamide;Methyl4-({1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoate;4-({1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-4-oxobutanoicacid;N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}pyridine-2-carboxamide;N-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;Methyl3-({(3S)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}amino)-3-oxopropanoate;N-1-{(3S)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}-N-2-,N-2-dimethylglycinamide;Benzyl(3R)-1-[(2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}nicotinamide;N-{(3R)-1-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-yl}isonicotinamide;5′-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-2,2′-bithiophene-5-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide;(E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide compound with4-chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide(1:1);6-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamideformate;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide;6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide;MethylN-[(5′-chloro-2,2′-bithien-5-yl)sulfonyl]-N-(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;5′-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl)-2,2′-bithiophene-5-sulfonamide;6-Chloro-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-methyl-N-{(3R)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-(3-methylpiperidin-1-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-[1-((2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]acetamide;6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate;N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine;6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide;6-Chloro-N-methyl-N-((3S)-1-{(1S)-1-methyl-2-[(2R)-2-methylpiperidin-1-yl]-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide;MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinate;N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycine;N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}glycinamide;6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-oxo-2-piperidin-1-ylethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide;N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinamide;MethylN-[(6-chloro-2-naphthyl)sulfonyl]-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)glycinateformate;6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}-2-oxopyrrolidin-3-yl)-N-(2-oxobutyl)naphthalene-2-sulfonamide;N-[1-((2R)-2-{(3S)-3-[[(6-Chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoyl)piperidin-3-yl]benzamide;6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-(3-[(1H-pyrrol-2-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(pyridin-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-oxo-2-{3-[(1H-pyrazol-3-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide;Benzyl(3S)-1-[(2S)-2-((3S)-3-}[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]piperidin-3-ylcarbamate;N-((3S)-1-{(1S)-2-[(3S)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide;andN-((3S)-1-{(1S)-2-[(3R)-3-Aminopiperidin-1-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)-6-chloronaphthalene-2-sulfonamide.11. A compound according to any one of claims 1-10 for use in therapy.12. A pharmaceutical composition comprising a compound according to anyone of claims 1-10 together with a pharmaceutical carrier and/orexcipient.
 13. Use of a compound according to any one of claims 1-10 forthe manufacture of a medicament for the treatment of a patient sufferingfrom a condition susceptible to amelioration by a Factor Xa inhibitor.14. A method of treating a patient suffering from a conditionsusceptible to amelioration by a Factor Xa inhibitor comprisingadministering a therapeutically effective amount of a compound accordingto any one of claims 1-10.
 15. A process for preparing a compound offormula (I) which comprises: (a) reacting a compound of formula (II)with a compound of formula (III):

OR: (b) reacting a compound of formula (XV) with a compound of formula(VI):

OR: (c) reacting a compound of formula (XVI) with a compound of formula(VIII):